Compounds Capable of Activating Cholinergic Receptors

ABSTRACT

Compounds incorporating aryl substituted olefinic amine are provided. Representative compounds are (4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine, (4E)-N-methyl-5-(5-pyrimidinyl)-4-penten-2-amine, (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine, (4E)-N-methyl-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine, (2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine, (2R)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine, (4E)-N-methyl-5-(5-bromo-3-pyridyl)-4-penten-2-amine, (4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine, (2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine, (4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine and (2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/379,443, filed Apr. 20, 2006; which is a continuation of U.S.application Ser. No. 11/181,055, filed Jul. 14, 2005 (now U.S. Pat. No.7,060,826); which is a continuation of U.S. application Ser. No.11/048,212, filed Feb. 1, 2005 (abandoned); which is a continuation ofU.S. application Ser. No. 09/522,117 filed Mar. 9, 2000 (abandoned);which is a continuation of U.S. application Ser. No. 09/098,285, filedJun. 16, 1998 (abandoned), the disclosures of which are incorporatedherein by reference in their entirety.

BACKGROUND OF THE INVENTION

The present invention relates to compounds capable of activatingnicotinic cholinergic receptors, for example, as agonists of specificnicotinic receptor subtypes.

Nicotine has been proposed to have a number of pharmacological effects.See, for example, Pullan et al. N. Engl. J. Med. 330:811-815 (1994).Certain of those effects may be related to effects upon neurotransmitterrelease. See for example, Sjak-shie et al., Brain Res. 624:295 (1993),where neuroprotective effects of nicotine are proposed. Release ofacetylcholine and dopamine by neurons upon administration of nicotinehas been reported by Rowell et al., J. Neurochem. 43:1593 (1984); Rapieret al., J. Neurochem. 50:1123 (1988); Sandor et al., Brain Res. 567:313(1991) and Vizi, Br. J. Pharmacol. 47:765 (1973). Release ofnorepinephrine by neurons upon administration of nicotine has beenreported by Hall et al., Biochem. Pharmacol. 21:1829 (1972). Release ofserotonin by neurons upon administration of nicotine has been reportedby Hery et al., Arch. Int. Pharmacodyn. Ther. 296:91 (1977). Release ofglutamate by neurons upon administration of nicotine has been reportedby Toth et al., Neurochem Res. 17:265 (1992). In addition, nicotinereportedly potentiates the pharmacological behavior of certainpharmaceutical compositions used for the treatment of certain disorders.See, Sanberg et al., Pharmacol. Biochem. & Behavior 46:303 (1993);Harsing et al., J. Neurochem. 59:48 (1993) and Hughes, Proceedings fromIntl. Symp. Nic. S40 (1994). Furthermore, various other beneficialpharmacological effects of nicotine have been proposed. See, Decina etal., Biol. Psychiatry 28:502 (1990); Wagner et al., Pharmacopsychiatry21:301 (1988); Pomerleau et al., Addictive Behaviors 9:265 (1984);Onaivi et al., Life Sci. 54(3):193 (1994); Tripathi et al., JPET 221:91-96 (1982) and Hamon, Trends in Pharmacol. Res. 15:36.

Various nicotinic compounds have been reported as being useful fortreating a wide variety of conditions and disorders. See, for example,Williams et al. DN&P 7(4):205-227 (1994), Arneric et al., CNS Drug Rev.1(1):1-26 (1995), Arneric et al., Exp. Opin. Invest. Drugs 5(1):79-100(1996), Bencherif et al., JPET 279:1413 (1996), Lippiello et al., JPET279:1422 (1996), Damaj et al., Neuroscience (1997), Holladay et al., J.Med. Chem. 40(28): 4169-4194 (1997), Bannon et al., Science 279: 77-80(1998), PCT WO 94/08992, PCT WO 96/31475, and U.S. Pat. No. 5,583,140 toBencherif et al., U.S. Pat. No. 5,597,919 to Dull et al., U.S. Pat. No.5,604,231 to Smith et al. and U.S. Pat. No. 5,616,716 to Dull et al.Nicotinic compounds are reported as being particularly useful fortreating a wide variety of Central Nervous System (CNS) disorders.

CNS disorders are a type of neurological disorder. CNS disorders can bedrug induced; can be attributed to genetic predisposition, infection ortrauma; or can be of unknown etiology. CNS disorders compriseneuropsychiatric disorders, neurological diseases and mental illnesses;and include neurodegenerative diseases, behavioral disorders, cognitivedisorders and cognitive affective disorders. There are several CNSdisorders whose clinical manifestations have been attributed to CNSdysfunction (i.e., disorders resulting from inappropriate levels ofneurotransmitter release, inappropriate properties of neurotransmitterreceptors, and/or inappropriate interaction between neurotransmittersand neurotransmitter receptors). Several CNS disorders can be attributedto a cholinergic deficiency, a dopaminergic deficiency, an adrenergicdeficiency and/or a serotonergic deficiency. CNS disorders of relativelycommon occurrence include presenile dementia (early onset Alzheimer'sdisease), senile dementia (dementia of the Alzheimer's type),Parkinsonism including Parkinson's disease, Huntington's chorea, tardivedyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety,dyslexia, schizophrenia and Tourette's syndrome.

It would be desirable to provide a useful method for the prevention andtreatment of a condition or disorder by administering a nicotiniccompound to a patient susceptible to or suffering from such a conditionor disorder. It would be highly beneficial to provide individualssuffering from certain disorders (e.g., CNS diseases) with interruptionof the symptoms of those disorders by the administration of apharmaceutical composition containing an active ingredient havingnicotinic pharmacology and which has a beneficial effect (e.g., upon thefunctioning of the CNS), but which does not provide any significantassociated side effects. It would be highly desirable to provide apharmaceutical composition incorporating a compound which interacts withnicotinic receptors, such as those which have the potential to affectthe functioning of the CNS, but which compound when employed in anamount sufficient to affect the functioning of the CNS, does notsignificantly affect those receptor subtypes which have the potential toinduce undesirable side effects (e.g., appreciable activity at skeletalmuscle and ganglia sites).

SUMMARY OF THE INVENTION

The present invention relates to aryl substituted olefinic aminecompounds. Representative compounds are(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-pyrimidinyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-bromo-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine,(2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine and(2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine. Thepresent invention also relates to methods for synthesizing certain arylsubstituted olefinic amine compounds, such as the compounds of thepresent invention. Of particular interest are isolated enantiomericcompounds (i.e., compounds in a substantially pure form, as opposed toracemic mixtures), and methods for synthesizing such enantiomericcompounds in substantially pure form.

The present invention also relates to methods for the prevention ortreatment of a wide variety of conditions or disorders, and particularlythose disorders characterized by dysfunction of nicotinic cholinergicneurotransmission including disorders involving neuromodulation ofneurotransmitter release, such as dopamine release. The presentinvention also relates to methods for the prevention or treatment ofdisorders, such as central nervous system (CNS) disorders, which arecharacterized by an alteration in normal neurotransmitter release. Thepresent invention also relates to methods for the treatment of certainconditions (e.g., a method for alleviating pain). The methods involveadministering to a subject an effective amount of a compound of thepresent invention.

The present invention, in another aspect, relates to a pharmaceuticalcomposition comprising an effective amount of a compound of the presentinvention. Such a pharmaceutical composition incorporates a compoundwhich, when employed in effective amounts, has the capability ofinteracting with relevant nicotinic receptor sites of a subject, andhence has the capability of acting as a therapeutic agent in theprevention or treatment of a wide variety of conditions and disorders,particularly those disorders characterized by an alteration in normalneurotransmitter release. Preferred pharmaceutical compositions comprisecompounds of the present invention.

The pharmaceutical compositions of the present invention are useful forthe prevention and treatment of disorders, such as CNS disorders, whichare characterized by an alteration in normal neurotransmitter release.The pharmaceutical compositions provide therapeutic benefit toindividuals suffering from such disorders and exhibiting clinicalmanifestations of such disorders in that the compounds within thosecompositions, when employed in effective amounts, have the potential to(i) exhibit nicotinic pharmacology and affect relevant nicotinicreceptors sites (e.g., act as a pharmacological agonist to activatenicotinic receptors), and (ii) elicit neurotransmitter secretion, andhence prevent and suppress the symptoms associated with those diseases.In addition, the compounds are expected to have the potential to (i)increase the number of nicotinic cholinergic receptors of the brain ofthe patient, (ii) exhibit neuroprotective effects and (iii) whenemployed in effective amounts do not cause appreciable adverse sideeffects (e.g., significant increases in blood pressure and heart rate,significant negative effects upon the gastro-intestinal tract, andsignificant effects upon skeletal muscle). The pharmaceuticalcompositions of the present invention are believed to be safe andeffective with regards to prevention and treatment of a wide variety ofconditions and disorders.

The foregoing and other aspects of the present invention are explainedin detail in the detailed description and examples set forth below.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention include compounds of the formula:

where each of X and X′ are individually nitrogen or carbon bonded to asubstituent species characterized as having a sigma m value greater than0, often greater than 0.1, and generally greater than 0.2, and evengreater than 0.3; less than 0 and generally less than −0.1; or 0; asdetermined in accordance with Hansch et al., Chem. Rev. 91:165 (1991); mis an integer and n is an integer such that the sum of m plus n is 1, 2,3, 4, 5, 6, 7, or 8, preferably is 1, 2, or 3, and most preferably is 2or 3; the wavy line in the structure indicates that the compound canhave the cis (Z) or trans (E) form; E^(I), E^(II), E^(III), E_(IV),E^(V) and E^(VI) individually represent hydrogen or lower alkyl (e.g.,straight chain or branched alkyl including C₁-C₈, preferably C₁-C₅, suchas methyl, ethyl, or isopropyl) or halo substituted lower alkyl (e.g.,straight chain or branched alkyl including C₁-C₈, preferably C₁-C₅, suchas trifluoromethyl or trichloromethyl), and at least one of E^(I),E^(II), E^(III), E^(IV), E^(V) and E^(VI) is non-hydrogen and theremaining E^(I), E^(II), E^(III), E^(IV), E^(V) and E^(VI) are hydrogen;and Z′ and Z″ individually represent hydrogen or lower alkyl (e.g.,straight chain or branched alkyl including C₁-C₈, preferably C₁-C₅, suchas methyl, ethyl, or isopropyl), and preferably at least one of Z′ andZ″ is hydrogen, and most preferably Z′ is hydrogen and Z″ is methyl;alternatively Z′ is hydrogen and Z″ represents a ring structure(cycloalkyl or aromatic), such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, adamantyl, quinuclidinyl, pyridyl, quinolinyl,pyrimidinyl, phenyl, benzyl (where any of the foregoing can be suitablysubstituted with at least one substituent group, such as alkyl, halo, oramino substituents); alternatively Z′, Z″, and the associated nitrogenatom can form a ring structure such as aziridinyl, azetidinyl,pyrollidinyl, piperidinyl, quinuclidinyl, piperazinyl, or morpholinyl.More specifically, X and X′ include N, C—H, C—F, C—Cl, C—Br, C—I, C—R′,C—NR′R″, C—CF₃, C—OH, C—CN, C—NO₂, C—C₂R′, C—SH, C—SCH₃, C—N₃, C—SO₂CH₃,C—OR′, C—SR′, C—C(═O)NR′R″, C—NR′C(═O)R′, C—C(═O)R′, C—C(═O)OR′,C(CH₂)_(q)OR′, C—OC(═O)R′, COC(═O)NR′R″ and C—NR′C(═O)OR′ where R′ andR″ are individually hydrogen or lower alkyl (e.g., C₁-C₁₀ alkyl,preferably C₁-C₅ alkyl, and more preferably methyl, ethyl, isopropyl orisobutyl), an aromatic group-containing species or a substitutedaromatic group-containing species, and q is an integer from 1 to 6. R′and R″ can be straight chain or branched alkyl, or R′ and R″ can form acycloalkyl functionality (e.g., cyclopropyl cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, adamantyl, and quinuclidinyl). Representativearomatic group-containing species include pyridyl, quinolinyl,pyrimidinyl, phenyl, and benzyl (where any of the foregoing can besuitably substituted with at least one substituent group, such as alkyl,halo, or amino substituents). Other representative aromatic ring systemsare set forth in Gibson et al., J. Med. Chem. 39:4065 (1996). When X andX′ represent a carbon atom bonded to a substituent species, thatsubstituent species often has a sigma m value which is between about−0.3 and about 0.75, and frequently between about −0.25 and about 0.6.In certain circumstances the substituent species is characterized ashaving a sigma m value not equal to 0. A, A′ and A″ individuallyrepresent those species described as substituent species to the aromaticcarbon atom previously described for X and X′; and usually includehydrogen, halo (e.g., F, Cl, Br, or I), alkyl (e.g., lower straightchain or branched C₁₋₈ alkyl, but preferably methyl or ethyl), or NX″X′″where X″ and X′″ are individually hydrogen or lower alkyl, includingC₁-C₈, preferably C₁-C₅ alkyl. In addition, it is highly preferred thatA is hydrogen, it is preferred that A′ is hydrogen, and normally A″ ishydrogen. Generally, both A and A′ are hydrogen; sometimes A and A′ arehydrogen, and A″ is amino, methyl or ethyl; and often A, A′ and A″ areall hydrogen. In a preferred embodiment, m is 1 or 2, n is 1, E^(I),E^(II), E^(III), E^(IV) and E^(VI) each are hydrogen, and E^(V) is alkyl(e.g., methyl). Depending upon the identity and positioning of eachindividual E^(I), E^(II), E^(III), E_(IV), E^(V) and E^(VI), certaincompounds can be optically active. Additionally, compounds of thepresent invention can have chiral centers within the alkenyl side chaine.g., the compound can have an R or S configuration depending on theselection of E^(III), E^(IV), E^(V) and E^(VI), with the S configurationbeing preferred. Depending upon E^(I), E^(II), E^(III), E^(IV), E^(V)and E^(VI), compounds of the present invention have chiral centers, andthe present invention relates to racemic mixtures of such compounds aswell as enantiomeric compounds. Typically, the selection of m, n, E^(I),E^(II), E^(III), E^(IV), E^(V) and E^(VI) is such that up to about 4,and frequently up to 3, and usually 1 or 2, of the substituentsdesignated as E^(I), E^(II), E^(III), E^(IV), E^(V) and E^(VI) arenon-hydrogen substituents (i.e., substituents such as lower alkyl orhalo-substituted lower alkyl). Typically, X is CH, CBr or COR. Mostpreferably, X′ is nitrogen.

Of particular interest are compounds of the formula:

where m, E^(I), E^(II), E^(III), E^(IV), X, Z′, Z″, A, A′ and A″ are asdefined hereinbefore.

Representative compounds of the present invention are (3E) and(3Z)-N-methyl-4-(3-pyridyl)-2-methyl-3-buten-1-amine, (3E) and(3Z)-N-methyl-4-(3-pyridyl)-3-methyl-3-buten-1-amine, (5E) and(5Z)-N-methyl-6-(3-pyridyl)-5-hexen-3-amine, (4E) and(4Z)-N-methyl-5-(3-pyridyl)-2-methyl-4-penten-2-amine, (4E) and(4Z)-N-methyl-5-(3-pyridyl)-3-methyl-4-penten-2-amine, (4E) and(4Z)-N-methyl-5-(3-pyridyl)-4-penten-2-amine, (4E) and(4Z)-N-methyl-5-(3-pyridyl)-1,1,1-trifluoro-4-penten-2-amine, (4E) and(4Z)-N-methyl-5-(3-pyridyl)-4-methyl-4-penten-1-amine, (4E) and(4Z)-N-methyl-5-(3-pyridyl)-4-methyl-4-penten-2-amine, (1E) and(1Z)-N-methyl-1-(3-pyridyl)-1-octen-4-amine, (1E) and(1Z)-N-methyl-1-(3-pyridyl)-5-methyl-1-hepten-4-amine, (5E) and(5Z)-N-methyl-6-(3-pyridyl)-5-methyl-5-hexen-2-amine, (5E) and(5Z)-N-methyl-6-(3-pyridyl)-5-hexen-2-amine, (5E) and(5Z)-N-methyl-6-(3-pyridyl)-5-methyl-5-hexen-3-amine, (3E) and(3Z)-4-(3-pyridyl)-2-methyl-3-buten-1-amine, (3E) and(3Z)-4-(3-pyridyl)-3-methyl-3-buten-1-amine, (5E) and(5Z)-6-(3-pyridyl)-5-hexen-3-amine, (4E) and(4Z)-5-(3-pyridyl)-2-methyl-4-penten-2-amine, (4E) and(4Z)-5-(3-pyridyl)-3-methyl-4-penten-2-amine, (4E) and(4Z)-5-(3-pyridyl)-4-penten-2-amine, (4E) and(4Z)-5-(3-pyridyl)-1,1,1-trifluoro-4-penten-2-amine, (4E) and(4Z)-5-(3-pyridyl)-4-methyl-4-penten-1-amine, (4E) and(4Z)-5-(3-pyridyl)-4-methyl-4-penten-2-amine, (1E) and(1Z)-1-(3-pyridyl)-1-octen-4-amine, (5E) and(5Z)-6-(3-pyridyl)-5-methyl-5-hexen-2-amine, (5E) and(5Z)-6-(3-pyridyl)-5-hexen-2-amine, and (5E) and(5Z)-6-(3-pyridyl)-5-methyl-5-hexen-3-amine. See, U.S. Pat. No.5,616,716 to Dull et al.

The manner in which aryl substituted olefinic amine compounds of thepresent invention are synthetically produced can vary.(E)-metanicotine-type compounds can be prepared using the techniques setforth by Löffler et al., Chem. Ber., 42, pp. 3431-3438 (1909) andLaforge, J.A.C.S., 50, p. 2477 (1928) from substituted nicotine-typecompounds. Certain 6-substituted metanicotine-type compounds can beprepared from the corresponding 6-substituted nicotine-type compoundsusing the general methods of Acheson et al., J. Chem. Soc., PerkinTrans. 1, 2, pp. 579-585 (1980). The requisite precursors for suchcompounds, 6-substituted nicotine-type compounds, can be synthesizedfrom 6-substituted nicotinic acid esters using the general methodsdisclosed by Rondahl, Acta Pharm. Suec., 14, pp 113-118 (1977).Preparation of certain 5-substituted metanicotine-type compounds can beaccomplished from the corresponding 5-substituted nicotine-typecompounds using the general method taught by Acheson et al., J. Chem.Soc., Perkin Trans. 1, 2, pp. 579-585 (1980). The 5-halo-substitutednicotine-type compounds (e.g., fluoro- and bromo-substitutednicotine-type compounds) and the 5-amino nicotine-type compounds can beprepared using the general procedures disclosed by Rondahl, Act. Pharm.Suec., 14, pp. 113-118 (1977). The 5-trifluoromethyl nicotine-typecompounds can be prepared using the techniques and materials set forthin Ashimori et al., Chem. Pharm. Bull., 38(9), pp. 2446-2458 (1990) andRondahl, Acta Pharm. Suec., 14, pp. 113-118 (1977).

Furthermore, preparation of certain metanicotine-type compounds can beaccomplished using a palladium catalyzed coupling reaction of anaromatic halide and a terminal olefin containing a protected aminesubstituent, removal of the protective group to obtain a primary amine,and optional alkylation to provide a secondary or tertiary amine. Inparticular, certain metanicotine-type compounds can be prepared bysubjecting a 3-halo-substituted, 5-substituted pyridine compound or a5-halo-substituted pyrimidine compound to a palladium catalyzed couplingreaction using an olefin possessing a protected amine functionality(e.g., such an olefin provided by the reaction of a phthalimide saltwith 3-halo-1-propene, 4-halo-1-butene, 5-halo-1-pentene or6-halo-1-hexene). See, Frank et al., J. Org. Chem., 43(15), pp.2947-2949 (1978) and Malek et al., J. Org. Chem., 47, pp. 5395-5397(1982). Alternatively, certain metanicotine-type compounds can beprepared by coupling an N-protected, modified amino acid residue, suchas 4-(N-methyl-N-tert-butyloxycarbonyl)aminobutyric acid methyl ester,with an aryl lithium compound, as can be derived from a suitable arylhalide and butyl lithium. The resulting N-protected aryl ketone is thenchemically reduced to the corresponding alcohol, converted to the alkylhalide, and subsequently dehydrohalogenated to introduce the olefinfunctionality. Removal of the N-protecting group then affords thedesired metanicotine-type compound.

There are a number of different methods for providing(Z)-metanicotine-type compounds. In one method, (Z)-metanicotine-typecompounds can be synthesized from nicotine-type compounds as a mixtureof E and Z isomers; and the (Z)-metanicotine-type compounds can then beseparated by chromatography using the types of techniques disclosed bySprouse et al., Abstracts of Papers, p. 32, Coresta/TCRC JointConference (1972). In another method, metanicotine-type compounds can beprepared by the controlled hydrogenation of the corresponding acetyleniccompound (e.g., an N-methyl-4-(3-pyridinyl)-3-butyn-1-amine typecompound). For example, certain 5-substituted (Z)-metanicotine-typecompounds and certain 6-substituted (Z)-metanicotine-type compounds canbe prepared from 5-substituted-3-pyridinecarboxaldehydes and6-substituted-3-pyridinecarboxaldehydes, respectively. Representativesynthetic techniques for (Z)-metanicotine-type compounds are set forthin U.S. Pat. No. 5,597,919 to Dull et al.

There are a number of methods by which the (Z)-olefinic isomers of arylsubstituted olefinic amine compounds can be synthetically produced. Inone approach, the (Z)-isomers of aryl substituted olefinic aminecompounds can be prepared by the controlled hydrogenation of thecorresponding alkynyl compounds (e.g., aN-methyl-5-(3-pyridyl)-4-butyn-2-amine-type compound) using commerciallyavailable Lindlar catalyst (Aldrich Chemical Company) using themethodology set forth in H. Lindlar et al., Org. Syn. 46: 89 (1966). Therequisite alkynyl compounds can be prepared by the palladium catalyzedcoupling of an aromatic halide, preferably a 3-bromopyridine-type or a3-iodopyridine-type compound with an alkynyl side chain compound (e.g.,an N-methyl-4-pentyn-2-amine-type compound). Typically the methodologyset forth in L. Bleicher et al., Synlett. 1115 (1995) is used for thepalladium catalyzed coupling of an aryl halide with a monosubstitutedalkyne in the presence of copper(I) iodide and triphenylphosphine andpotassium carbonate as a base. Alkynyl compounds such asN-methyl-4-pentyn-2-amine can be prepared from commercially available4-pentyn-2-ol (Aldrich Chemical Company) by treatment withp-toluenesulfonyl chloride in pyridine, followed by reaction of theresulting 4-pentyn-2-ol p-toluenesulfonate with excess methylamineeither as a 40% aqueous solution or as a 2.0 M solution intetrahydrofuran. In some instances it may be necessary to protect theamino functionality of the N-methyl-4-pentyn-2-amine-type compound bytreatment with di-tert-butyl dicarbonate to give the tert-butoxycarbonylprotected amine-type compound. Such protected amine compounds mayundergo the palladium catalyzed coupling with aryl halides and thesubsequent controlled hydrogenation of the resulting alkynyl compoundmore easily than the unprotected amine compounds. Thetert-butoxycarbonyl protecting group can be easily removed using astrong acid such as trifluoroacetic acid to yield the (Z)-olefinicisomers of aryl substituted olefinic amine compounds.

The methods by which aryl substituted olefinic amine compounds of thepresent invention can be synthetically produced can vary. An olefinicalcohol, such as 4-penten-2-ol, is condensed with an aromatic halide,such as 3-bromopyridine or 3-iodopyridine. Typically, the types ofprocedures set forth in Frank et al., J. Org. Chem., 43, pp. 2947-2949(1978) and Malek et al., J. Org. Chem., 47, pp. 5395-5397 (1982)involving a palladium-catalyzed coupling of an olefin and an aromatichalide are used. The olefinic alcohol optionally can be protected as at-butyldimethylsilyl ether prior to the coupling. Desilylation thenproduces the olefinic alcohol. The alcohol condensation product then isconverted to an amine using the type of procedures set forth in deCostaet al., J. Org. Chem., 35, pp. 4334-4343 (1992). Typically, the alcoholcondensation product is converted to the aryl substituted olefinic amineby activation of the alcohol using methanesulfonyl chloride orp-toluenesulfonyl chloride, followed by mesylate or tosylatedisplacement using ammonia, or a primary or secondary amine. Thus, whenthe amine is ammonia, an aryl substituted olefinic primary aminecompound is provided; when the amine is a primary amine such asmethylamine or cyclobutylamine, an aryl substituted olefinic secondaryamine compound is provided; and when the amine is a secondary amine suchas dimethylamine or pyrrolidine, an aryl substituted olefinic tertiaryamine compound is provided. Other representative olefinic alcoholsinclude 4-penten-1-ol, 5-hexen-2-ol, 5-hexen-3-ol,3-methyl-3-buten-1-ol, 2-methyl-3-buten-1-ol, 4-methyl-4-penten-1-ol,4-methyl-4-penten-2-ol, 1-octen-4-ol, 5-methyl-1-hepten-4-ol,4-methyl-5-hexen-2-ol, 5-methyl-5-hexen-2-ol, 5-hexen-2-ol and5-methyl-5-hexen-3-ol. Trifluormethyl-substituted olefinic alcohols,such as 1,1,1-trifluoro-4-penten-2-ol, can be prepared from1-ethoxy-2,2,2-trifluoro-ethanol and allyltrimethylsilane using theprocedures of Kubota et al., Tetrahedron Letters, Vol. 33(10), pp.1351-1354 (1992), or from trifluoroacetic acid ethyl ester andallyltributylstannane using the procedures of Ishihara et al.,Tetrahedron Letters, Vol. 34(56), pp. 5777-5780 (1993). Certain olefinicalcohols are optically active, and can be used as enantiomeric mixturesor as pure enantiomers in order to provide the corresponding opticallyactive forms of aryl substituted olefinic amine compounds. When anolefinic allylic alcohol, such as methallyl alcohol, is reacted with anaromatic halide, an aryl substituted olefinic aldehyde is produced; andthe resulting aldehyde can be converted to an aryl substituted olefinicamine compound by reductive amination (e.g., by treatment using an alkylamine and sodium cyanoborohydride). Preferred aromatic halides are3-bromopyridine-type compounds and 3-iodopyridine-type compounds.Typically, substituent groups of such 3-halopyridine-type compounds aresuch that those groups can survive contact with those chemicals (e.g.,tosylchloride and methylamine) and the reaction conditions experiencedduring the preparation of the aryl substituted olefinic amine compound.Alternatively, substituents such as —OH, —NH₂ and —SH can be protectedas corresponding acyl compounds, or substituents such as —NH₂ can beprotected as a phthalimide functionality.

The manner in which certain aryl substituted olefinic amine compoundspossessing a branched side chain, such as(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine, are providedcan vary. By using one synthetic approach, the latter compound can besynthesized in a convergent manner, in which the side chain,N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine is coupled with the3-substituted 5-halo-substituted pyridine, 5-bromo-3-isopropoxypyridine,under Heck reaction conditions, followed by removal of thetert-butoxycarbonyl protecting group. Typically, the types of proceduresset forth in W. C. Frank et al., J. Org. Chem. 43: 2947 (1978) and N. J.Malek et al., J. Org. Chem. 47: 5395 (1982) involving apalladium-catalyzed coupling of an olefin and an aromatic halide areused. The required N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine canbe synthesized as follows: (i) commercially available 4-penten-2-ol(Aldrich Chemical Company, Lancaster Synthesis Inc.) can be treated withp-toluenesulfonyl chloride in pyridine to yield 4-penten-2-olp-toluenesulfonate, previously described by T. Michel, et al., LiebigsAnn. 11: 1811 (1996); (ii) the resulting tosylate can be heated with 20molar equivalents of methylamine as a 40% aqueous solution to yieldN-methyl-4-penten-2-amine; and (iii) the resulting amine, such aspreviously mentioned by A. Viola et al., J. Chem. Soc., Chem. Commun.(21): 1429 (1984), can be allowed to react with 1.2 molar equivalents ofdi-tert-butyl dicarbonate in dry tetrahydrofuran to yield the sidechain, N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine. Thehalo-substituted pyridine, (e.g., 5-bromo-3-isopropoxypyridine) can besynthesized by two different routes. In one preparation,3,5-dibromopyridine is heated at 140° C. for 14 hours with 2 molarequivalents of potassium isopropoxide in dry isopropanol in the presenceof copper powder (5%, w/w of the 3,5-dibromopyridine) in a sealed glasstube to yield 5-bromo-3-isopropoxypyridine. A second preparation of5-bromo-3-isopropoxypyridine from 5-bromonicotinic acid can be performedas follows: (i) 5-Bromonicotinic acid is converted to5-bromonicotinamide by treatment with thionyl chloride, followed byreaction of the intermediate acid chloride with aqueous ammonia; (ii)the resulting 5-bromonicotinamide, previously described by C. V. Grecoet al., J. Heteocyclic Chem. 7(4): 761 (1970), is subjected to Hofmanndegradation by treatment with sodium hydroxide and a 70% solution ofcalcium hypochlorite; and (iii) the resulting 3-amino-5-bromopyridine,previously described by C. V. Greco et al., J. Heteocyclic Chem. 7(4):761 (1970), can be converted to 5-bromo-3-isopropoxypyridine bydiazotization with isoamyl nitrite under acidic conditions, followed bytreatment of the intermediate diazonium salt with isopropanol to yield5-bromo-3-isopropoxypyridine. The palladium-catalyzed coupling of5-bromo-3-isopropoxypyridine andN-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine is carried out inacetonitrile-triethylamine (2:1, v,v) using a catalyst consisting of 1mole % palladium(II) acetate and 4 mole % tri-o-tolylphosphine. Thereaction can be carried out by heating the components at 80° C. for 20hours to yield(4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine.Removal of the tert-butoxycarbonyl protecting group can be accomplishedby treatment with 30 molar equivalents of trifluoroacetic acid inanisole at 0° C. to afford(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine.

The manner in which certain aryl substituted olefinic amine compoundspossessing a branched side chain are provided can vary. Using onesynthetic approach, a compound such as(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine can besynthesized by coupling a halo-substituted pyridine,5-bromo-3-methoxypyridine with an olefin containing a secondary alcoholfunctionality, 4-penten-2-ol, under Heck reaction conditions; and theresulting pyridyl alcohol intermediate can be converted to itsp-toluenesulfonate ester, followed by treatment with methylamine.Typically, the types of procedures set forth in W. C. Frank et al., J.Org. Chem. 43: 2947 (1978) and N. J. Malek et al., J. Org. Chem. 47:5395 (1982) involving a palladium-catalyzed coupling of an olefin and anaromatic halide are used. The required halo-substituted pyridine,5-bromo-3-methoxypyridine is synthesized using methodology similar tothat described by H. J. den Hertog et al., Recl. Trav. Chim. Pays-Bas74:1171 (1955), namely by heating 3,5-dibromopyridine with 2.5 molarequivalents of sodium methoxide in dry methanol in the presence ofcopper powder (5%, w/w of the 3,5-dibromopyridine) in a sealed glasstube at 150° C. for 14 hours to produce 5-bromo-3-methoxypyridine. Theresulting 5-bromo-3-methoxypyridine, previously described by D. L.Comins, et al., J. Org. Chem. 55: 69 (1990), can be coupled with4-penten-2-ol in acetonitrile-triethylamine (1.1:1, v/v) using acatalyst consisting of 1 mole % palladium(II) acetate and 4 mole %tri-o-tolylphosphine. The reaction is carried out by heating thecomponents in a sealed glass tube at 140° C. for 14 hours to yield(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-ol. The resultingalcohol is treated with 2 molar equivalents of p-toluenesulfonylchloride in dry pyridine at 0° C. to produce(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-ol p-toluensulfonate.The tosylate intermediate is treated with 120-molar equivalents ofmethylamine as a 40% aqueous solution, containing a small amount ofethanol as a co-solvent to produce(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine.

The manner in which optically active forms of certain aryl substitutedolefinic amine compounds, such as(2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine, are provided canvary. In one synthetic approach, the latter type of compound issynthesized by coupling a halo-substituted pyridine, 3-bromopyridine,with an olefin possessing a chiral, secondary alcohol functionality,(2R)-4-penten-2-ol, under Heck reaction conditions. The resulting chiralpyridyl alcohol intermediate, (2R)-(4E)-5-(3-pyridyl)-4-penten-2-ol isconverted to its corresponding p-toluenesulfonate ester, which issubsequently treated with methylamine, resulting in tosylatedisplacement with inversion of configuration. Typically, the types ofprocedures set forth in W. C. Frank et al., J. Org. Chem. 43: 2947(1978) and N. J. Malek et al., J. Org. Chem. 47: 5395 (1982) involving apalladium-catalyzed coupling of an aromatic halide and an olefin areused. The chiral side chain, (2R)-4-penten-2-ol can be prepared bytreatment of the chiral epoxide, (R)-(+)-propylene oxide (commerciallyavailable from Fluka Chemical Company) with vinylmagnesium bromide intetrahydrofuran at low temperatures (−25 to −10° C.) using the generalsynthetic methodology of A. Kalivretenos, J. K. Stille, and L. S.Hegedus, J. Org. Chem. 56: 2883 (1991), to afford (2R)-4-penten-2-ol.The resulting chiral alcohol is subjected to a Heck reaction with3-bromopyridine in acetonitrile-triethylamine (1:1, v/v) using acatalyst consisting of 1 mole % palladium(II) acetate and 4 mole %tri-o-tolylphosphine. The reaction is done by heating the components at140° C. for 14 hours in a sealed glass tube, to produce the Heckreaction product, (2R)-(4E)-5-(3-pyridyl)-4-penten-2-ol. The resultingchiral pyridyl alcohol is treated with 3 molar equivalents ofp-toluenesulfonyl chloride in dry pyridine at 0° C., to afford thetosylate intermediate. The p-toluenesulfonate ester is heated with 82molar equivalents of methylamine as a 40% aqueous solution, containing asmall amount of ethanol as a co-solvent, to produce(2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine. In a similar manner,the corresponding aryl substituted olefinic amine enantiomer, such as(2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine, can be synthesized bythe Heck coupling of 3-bromopyridine and (2S)-4-penten-2-ol. Theresulting intermediate, (2S)-(4E)-5-(3-pyridyl)-4-penten-2-ol, isconverted to its p-toluenesulfonate, which is subjected to methylaminedisplacement. The chiral alcohol, (2S)-4-penten-2-ol, is prepared from(S)-(−)-propylene oxide (commercially available from Aldrich ChemicalCompany) using a procedure analogous to that described for thepreparation of (2R)-4-penten-2-ol from (R)-(+)-propylene oxide asreported by A. Kalivretenos, J. K. Stille, and L. S. Hegedus, J. Org.Chem. 56: 2883 (1991).

The present invention relates to a method for providing prevention of acondition or disorder to a subject susceptible to such a condition ordisorder, and for providing treatment to a subject suffering therefrom.For example, the method comprises administering to a patient an amountof a compound effective for providing some degree of prevention of theprogression of a CNS disorder (i.e., provide protective effects),amelioration of the symptoms of a CNS disorder, and amelioration of therecurrence of a CNS disorder. The method involves administering aneffective amount of a compound selected from the general formulae whichare set forth hereinbefore. The present invention relates to apharmaceutical composition incorporating a compound selected from thegeneral formulae which are set forth hereinbefore. Optically activecompounds can be employed as racemic mixtures or as enantiomers. Thecompounds can be employed in a free base form or in a salt form (e.g.,as pharmaceutically acceptable salts). Examples of suitablepharmaceutically acceptable salts include inorganic acid addition saltssuch as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate;organic acid addition salts such as acetate, galactarate, propionate,succinate, lactate, glycolate, malate, tartrate, citrate, maleate,fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; saltswith acidic amino acids such as aspartate and glutamate; alkali metalsalts such as sodium salt and potassium salt; alkaline earth metal saltssuch as magnesium salt and calcium salt; ammonium salt; organic basicsalts such as trimethylamine salt, triethylamine salt, pyridine salt,picoline salt, dicyclohexylamine salt, and N,N′-dibenzylethylenediaminesalt; and salts with basic amino acids such as lysine salt and argininesalt. The salts may be in some cases hydrates or ethanol solvates.Representative salts are provided as described in U.S. Pat. No.5,597,919 to Dull et al., U.S. Pat. No. 5,616,716 to Dull et al. andU.S. Pat. No. 5,663,356 to Ruecroft et al.

Compounds of the present invention are useful for treating those typesof conditions and disorders for which other types of nicotinic compoundshave been proposed as therapeutics. See, for example, Williams et al.DN&P 7(4):205-227 (1994), Arneric et al., CNS Drug Rev. 1(1):1-26(1995), Arneric et al., Exp. Opin. Invest. Drugs 5(1):79-100 (1996),Bencherif et al., JPET 279:1413 (1996), Lippiello et al., JPET 279:1422(1996), Damaj et al., Neuroscience (1997), Holladay et al., J. Med.Chem. 40(28): 4169-4194 (1997), Bannon et al., Science 279: 77-80(1998), PCT WO 94/08992, PCT WO 96/31475, and U.S. Pat. No. 5,583,140 toBencherif et al., U.S. Pat. No. 5,597,919 to Dull et al., and U.S. Pat.No. 5,604,231 to Smith et al. Compounds of the present invention can beused as analgesics, to treat ulcerative colitis, and to treatconvulsions such as those that are symptomatic of epilepsy. CNSdisorders which can be treated in accordance with the present inventioninclude presenile dementia (early onset Alzheimer's disease), seniledementia (dementia of the Alzheimer's type), Parkinsonism includingParkinson's disease, Huntington's chorea, tardive dyskinesia,hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia,schizophrenia and Tourette's syndrome.

The pharmaceutical composition also can include various other componentsas additives or adjuncts. Exemplary pharmaceutically acceptablecomponents or adjuncts which are employed in relevant circumstancesinclude antioxidants, free radical scavenging agents, peptides, growthfactors, antibiotics, bacteriostatic agents, immunosuppressives,anticoagulants, buffering agents, anti-inflammatory agents,anti-pyretics, time release binders, anaesthetics, steroids andcorticosteroids. Such components can provide additional therapeuticbenefit, act to affect the therapeutic action of the pharmaceuticalcomposition, or act towards preventing any potential side effects whichmay be posed as a result of administration of the pharmaceuticalcomposition. In certain circumstances, a compound of the presentinvention can be employed as part of a pharmaceutical composition withother compounds intended to prevent or treat a particular disorder.

The manner in which the compounds are administered can vary. Thecompounds can be administered by inhalation (e.g., in the form of anaerosol either nasally or using delivery articles of the type set forthin U.S. Pat. No. 4,922,901 to Brooks et al.); topically (e.g., in lotionform); orally (e.g., in liquid form within a solvent such as an aqueousor non-aqueous liquid, or within a solid carrier); intravenously (e.g.,within a dextrose or saline solution); as an infusion or injection(e.g., as a suspension or as an emulsion in a pharmaceuticallyacceptable liquid or mixture of liquids); intrathecally; intracerebroventricularly; or transdermally (e.g., using a transdermal patch).Although it is possible to administer the compounds in the form of abulk active chemical, it is preferred to present each compound in theform of a pharmaceutical composition or formulation for efficient andeffective administration. Exemplary methods for administering suchcompounds will be apparent to the skilled artisan. For example, thecompounds can be administered in the form of a tablet, a hard gelatincapsule or as a time release capsule. As another example, the compoundscan be delivered transdermally using the types of patch technologiesavailable from Novartis and Alza Corporation. The administration of thepharmaceutical compositions of the present invention can beintermittent, or at a gradual, continuous, constant or controlled rateto a warm-blooded animal, (e.g., a mammal such as a mouse, rat, cat,rabbit, dog, pig, cow, or monkey); but advantageously is preferablyadministered to a human being. In addition, the time of day and thenumber of times per day that the pharmaceutical formulation isadministered can vary. Administration preferably is such that the activeingredients of the pharmaceutical formulation interact with receptorsites within the body of the subject that affect the functioning of theCNS. More specifically, in treating a CNS disorder administrationpreferably is such so as to optimize the effect upon those relevantreceptor subtypes which have an effect upon the functioning of the CNS,while minimizing the effects upon muscle-type receptor subtypes. Othersuitable methods for administering the compounds of the presentinvention are described in U.S. Pat. No. 5,604,231 to Smith et al., thedisclosure of which is incorporated herein by reference in its entirety.

The appropriate dose of the compound is that amount effective to preventoccurrence of the symptoms of the disorder or to treat some symptoms ofthe disorder from which the patient suffers. By “effective amount”,“therapeutic amount” or “effective dose” is meant that amount sufficientto elicit the desired pharmacological or therapeutic effects, thusresulting in effective prevention or treatment of the disorder. Thus,when treating a CNS disorder, an effective amount of compound is anamount sufficient to pass across the blood-brain barrier of the subject,to bind to relevant receptor sites in the brain of the subject, and toactivate relevant nicotinic receptor subtypes (e.g., provideneurotransmitter secretion, thus resulting in effective prevention ortreatment of the disorder). Prevention of the disorder is manifested bydelaying the onset of the symptoms of the disorder. Treatment of thedisorder is manifested by a decrease in the symptoms associated with thedisorder or an amelioration of the recurrence of the symptoms of thedisorder. Relative to (E)-metanicotine, compounds of the presentinvention are less extensively metabolized (i.e., fewer metabolites areformed, and the rate of elimination from blood is slower) in mammaliansystems. As such, as compared to (E)-metanicotine, compounds of thepresent invention are capable of providing higher absolute plasmaconcentrations, and are capable of being maintained within a mammaliansystem for longer periods of time. Thus, compounds of the presentinvention are capable of providing comparable therapeutic effects of(E)-metanicotine at low doses.

The effective dose can vary, depending upon factors such as thecondition of the patient, the severity of the symptoms of the disorder,and the manner in which the pharmaceutical composition is administered.For human patients, the effective dose of typical compounds generallyrequires administering the compound in an amount sufficient to activaterelevant receptors to effect neurotransmitter (e.g., dopamine) releasebut the amount should be insufficient to induce effects on skeletalmuscles and ganglia to any significant degree. The effective dose ofcompounds will of course differ from patient to patient but in generalincludes amounts starting where CNS effects or other desired therapeuticeffects occur, but below the amount where muscular effects are observed.

Typically, the effective dose of compounds generally requiresadministering the compound in an amount of less than 5 mg/kg of patientweight. Often, the compounds of the present invention are administeredin an amount from 1 mg to less than 100 ug/kg of patient weight,frequently between about 10 ug to less than 100 ug/kg of patient weight,and preferably between about 10 ug to about 50 ug/kg of patient weight.For compounds of the present invention that do not induce effects onmuscle type nicotinic receptors at low concentrations, the effectivedose is less than 5 mg/kg of patient weight; and often such compoundsare administered in an amount from 50 ug to less than 5 mg/kg of patientweight. The foregoing effective doses typically represent that amountadministered as a single dose, or as one or more doses administered overa 24 hour period.

For human patients, the effective dose of typical compounds generallyrequires administering the compound in an amount of at least about 1,often at least about 10, and frequently at least about 25 ug/24hr./patient. For human patients, the effective dose of typical compoundsrequires administering the compound which generally does not exceedabout 500, often does not exceed about 400, and frequently does notexceed about 300 ug/24 hr./patient. In addition, administration of theeffective dose is such that the concentration of the compound within theplasma of the patient normally does not exceed 500 ng/ml, and frequentlydoes not exceed 100 ng/ml.

The compounds useful according to the method of the present inventionhave the ability to pass across the blood-brain barrier of the patient.As such, such compounds have the ability to enter the central nervoussystem of the patient. The log P values of typical compounds, which areuseful in carrying out the present invention are generally greater thanabout 0, often are greater than about 0.5, and frequently are greaterthan about 1. The log P values of such typical compounds generally areless than about 3.5, often are less than about 3, and sometimes are lessthan about 2.5. Log P values provide a measure of the ability of acompound to pass across a diffusion barrier, such as a biologicalmembrane. See, Hansch, et al., J. Med. Chem. 11:1 (1968).

The compounds useful according to the method of the present inventionhave the ability to bind to, and in most circumstances, cause activationof, nicotinic cholinergic receptors of the brain of the patient (e.g.,such as those receptors that modulate dopamine release). As such, suchcompounds have the ability to express nicotinic pharmacology, and inparticular, to act as nicotinic agonists. The receptor binding constantsof typical compounds useful in carrying out the present inventiongenerally exceed about 0.1 nM, often exceed about 1 nM, and frequentlyexceed about 10 uM. The receptor binding constants of such typicalcompounds generally are less than about 1 uM, often are less than about100 nM, and frequently are less than about 50 nM. Receptor bindingconstants provide a measure of the ability of the compound to bind tohalf of the relevant receptor sites of certain brain cells of thepatient. See, Cheng, et al., Biochem. Pharmacol. 22:3099 (1973).

The compounds useful according to the method of the present inventionhave the ability to demonstrate a nicotinic function by effectivelyeliciting ion flux through, and/or neurotransmitter secretion from,nerve ending preparations (e.g., thalamic or striatal synaptosomes). Assuch, such compounds have the ability to cause relevant neurons tobecome activated, and to release or secrete acetylcholine, dopamine, orother neurotransmitters. Generally, typical compounds useful in carryingout the present invention effectively provide for relevant receptoractivation in amounts of at least about 30 percent, often at least about50 percent, and frequently at least about 75 percent, of that maximallyprovided by (S)-(−)-nicotine. Generally, typical compounds useful incarrying out the present invention are more potent than (S)-(−)-nicotinein eliciting relevant receptor activation. Generally, typical compoundsuseful in carrying out the present invention effectively provide for thesecretion of dopamine in amounts of at least about 50 percent, often atleast about 75 percent, and frequently at least about 100 percent, ofthat maximally provided by (S)-(−)-nicotine. Certain compounds of thepresent invention can provide secretion of dopamine in an amount whichcan exceed that maximally provided by (S)-(−)-nicotine. Generally,typical compounds useful in carrying out the present invention are lesspotent than (S)-(−)-nicotine in eliciting neurotransmitter secretion,such as dopamine secretion.

The compounds of the present invention, when employed in effectiveamounts in accordance with the method of the present invention, lack theability to elicit activation of nicotinic receptors of human muscle toany significant degree. In that regard, the compounds of the presentinvention demonstrate poor ability to cause isotopic rubidium ion fluxthrough nicotinic receptors in cell preparations expressing muscle-typenicotinic acetylcholine receptors. Thus, such compounds exhibit receptoractivation constants or EC50 values (i.e., which provide a measure ofthe concentration of compound needed to activate half of the relevantreceptor sites of the skeletal muscle of a patient) which are extremelyhigh (i.e., greater than about 100 uM). Generally, typical preferredcompounds useful in carrying the present invention activate isotopicrubidium ion flux by less than 10 percent, often by less than 5 percent,of that maximally provided by S(−) nicotine.

The compounds of the present invention, when employed in effectiveamounts in accordance with the method of the present invention, areselective to certain relevant nicotinic receptors, but do not causesignificant activation of receptors associated with undesirable sideeffects. By this is meant that a particular dose of compound resultingin prevention and/or treatment of a CNS disorder, is essentiallyineffective in eliciting activation of certain ganglionic-type nicotinicreceptors. This selectivity of the compounds of the present inventionagainst those receptors responsible for cardiovascular side effects isdemonstrated by a lack of the ability of those compounds to activatenicotinic function of adrenal chromaffin tissue. As such, such compoundshave poor ability to cause isotopic rubidium ion flux through nicotinicreceptors in cell preparations derived from the adrenal gland.Generally, typical preferred compounds useful in carrying out thepresent invention activate isotopic rubidium ion flux by less than 10percent, often by less than 5 percent, of that maximally provided byS(−) nicotine.

Compounds of the present invention, when employed in effective amountsin accordance with the method of the present invention, are effectivetowards providing some degree of prevention of the progression of CNSdisorders, amelioration of the symptoms of CNS disorders, andamelioration to some degree of the recurrence of CNS disorders. However,such effective amounts of those compounds are not sufficient to elicitany appreciable side effects, as is demonstrated by decreased effects onpreparations believed to reflect effects on the cardiovascular system,or effects to skeletal muscle. As such, administration of compounds ofthe present invention provides a therapeutic window in which treatmentof certain CNS disorders is provided, and side effects are avoided. Thatis, an effective dose of a compound of the present invention issufficient to provide the desired effects upon the CNS, but isinsufficient (i.e., is not at a high enough level) to provideundesirable side effects. Preferably, effective administration of acompound of the present invention resulting in treatment of CNSdisorders occurs upon administration of less than ⅓, frequently lessthan ⅕, and often less than 1/10, that amount sufficient to cause anyside effects to a significant degree.

The following examples are provided to illustrate the present invention,and should not be construed as limiting thereof. In these examples, allparts and percentages are by weight, unless otherwise noted. Reactionyields are reported in mole percentages. Several commercially availablestarting materials are used throughout the following examples.3-Bromopyridine, 3,5-dibromopyridine, 5-bromonicotinic acid,5-bromopyrimidine, and 4-penten-2-ol were obtained from Aldrich ChemicalCompany or Lancaster Synthesis Inc. 2-Amino-5-bromo-3-methylpyridine waspurchased from Maybridge Chemical Company Ltd. (R)-(+)-propylene oxidewas obtained from Fluka Chemical Company, and (S)-(−)-propylene oxidewas obtained from Aldrich Chemical Company. Column chromatography wasdone using either Merck silica gel 60 (70-230 mesh) or aluminum oxide(activated, neutral, Brockmann I, standard grade, ˜150 mesh). Pressurereactions were done in a heavy wall glass pressure tube (185 mLcapacity), with Ace-Thread, and plunger valve available from Ace GlassInc. Reaction mixtures were typically heated using a high-temperaturesilicon oil bath, and temperatures refer to those of the oil bath. Thefollowing abbreviations are used in the following examples: CHCl₃ forchloroform, CH₂Cl₂ for dichloromethane, CH₃OH for methanol, DMF forN,N-dimethylformamide, and EtOAc for ethyl acetate, THF fortetrahydrofuran, and Et₃N for triethylamine.

EXAMPLE 1 Determination of Log P Value

Log P values, which have been used to assess the relative abilities ofcompounds to pass across the blood-brain barrier (Hansch, et al., J.Med. Chem. ii:l (1968)), were calculated using the Cerius² softwarepackage Version 3.5 by Molecular Simulations, Inc.

EXAMPLE 2 Determination of Binding to Relevant Receptor Sites

Binding of the compounds to relevant receptor sites was determined inaccordance with the techniques described in U.S. Pat. No. 5,597,919 toDull et al. Inhibition constants (Ki values), reported in nM, werecalculated from the IC₅₀ values using the method of Cheng et al.,Biochem, Pharmacol. 22:3099 (1973).

EXAMPLE 3 Determination of Dopamine Release

Dopamine release was measured using the techniques described in U.S.Pat. No. 5,597,919 to Dull et al. Release is expressed as a percentageof release obtained with a concentration of (S)-(−)-nicotine resultingin maximal effects. Reported EC₅₀ values are expressed in mM, andE_(max) values represent the amount released relative to(S)-(−)-nicotine on a percentage basis.

EXAMPLE 4 Determination of Rubidium Ion Release

Rubidium release was measured using the techniques described inBencherif et al., JPET, 279: 1413-1421 (1996). Reported EC₅₀ values areexpressed in nM, and E_(max) values represent the amount of rubidium ionreleased relative to 300 uM tetramethylammonium ion, on a percentagebasis.

EXAMPLE 5 Determination of Interaction with Muscle Receptors

The determination of the interaction of the compounds with musclereceptors was carried out in accordance with the techniques described inU.S. Pat. No. 5,597,919 to Dull et al. The maximal activation forindividual compounds (E_(max)) was determined as a percentage of themaximal activation induced by (S)-(−)-nicotine. Reported E_(max) valuesrepresent the amount released relative to (S)-(−)-nicotine on apercentage basis.

EXAMPLE 6 Determination of Interaction with Ganglion Receptors

The determination of the interaction of the compounds with ganglionicreceptors was carried out in accordance with the techniques described inU.S. Pat. No. 5,597,919 to Dull et al. The maximal activation forindividual compounds (E_(max)) was determined as a percentage of themaximal activation induced by (S)-(−)-nicotine. Reported E_(max) valuesrepresent the amount released relative to (S)-(−)-nicotine on apercentage basis.

EXAMPLE 7

Sample No. 1 is (4E)-N-methyl-5-(3-pyridyl)-4-penten-2-aminehemigalactarate, which was prepared in accordance with the followingtechniques:

(4E)-5-(3-Pyridyl)-4-penten-2-ol

A mixture of 3-bromopyridine (7.50 g, 47.46 mmol), 4-penten-2-ol (4.90g, 56.96 mmol), palladium(II) acetate (106 mg, 0.47 mmol),tri-o-tolylphosphine (575 mg, 1.89 mmol), triethylamine (28.4 mL, 204.11mmol) and acetonitrile (25 mL) was heated in a sealed glass tube at 140°C. for 14 h. The reaction mixture was cooled to ambient temperature,diluted with water, and extracted with chloroform (3×200 mL). Thecombined chloroform extracts were dried over sodium sulfate, filtered,and concentrated by rotary evaporation to give a pale-yellow oil (7.50g, 81.0%).

(4E)-5-(3-Pyridyl)-4-penten-2-ol p-Toluenesulfonate

To a stirred solution of (4E)-5-(3-pyridyl)-4-penten-2-ol (5.00 g, 30.67mmol) in dry pyridine (30 mL) at 0° C. was added p-toluenesulfonylchloride (8.77 g, 46.01 mmol). The reaction mixture was stirred for 24 hat ambient temperature. The pyridine was removed by rotary evaporation.Toluene (50 mL) was added to the residue and subsequently removed byrotary evaporation. The crude product was stirred with a saturatedsolution of sodium bicarbonate (100 mL) and extracted with chloroform(3×100 mL). The combined chloroform extracts were dried over sodiumsulfate, filtered, and concentrated by rotary evaporation. The crudeproduct was purified by column chromatography over aluminum oxide,eluting with ethyl acetate-hexane (3:7, v/v). Selected fractions werecombined and concentrated by rotary evaporation to give a viscous, brownoil (5.83 g, 60.1%).

(4E)-N-Methyl-5-(3-pyridyl)-4-penten-2-amine

A mixture of (4E)-5-(3-pyridyl)-4-penten-2-ol p-toluenesulfonate (5.60g, 17.66 mmol), methylamine (100 mL, 40% solution in water), and ethylalcohol (10 mL) was stirred at ambient temperature for 18 h. Theresulting solution was extracted with chloroform (3×100 mL). Thecombined chloroform extracts were dried over sodium sulfate, filtered,and concentrated by rotary evaporation. The crude product was purifiedby column chromatography over aluminum oxide, eluting with ethylacetate-methanol (7:3, v/v). Selected fractions were combined andconcentrated by rotary evaporation, producing an oil. Furtherpurification by vacuum distillation furnished 1.60 g (51.6%) of acolorless oil, bp 110-120° C. at 0.1 mm Hg.

(4E)-N-Methyl-5-(3-pyridyl)-4-penten-2-amine Hemigalactarate

(4E)-N-Methyl-5-(3-pyridyl)-4-penten-2-amine (1.60 g, 9.10 mmol) wasdissolved in ethyl alcohol (20 mL), assisted by warming to 60° C. Thewarm solution was treated with galactaric acid (955 mg, 4.54 mmol) inone portion, followed by the dropwise addition of water (0.5 mL). Thesolution was filtered while hot to remove some insoluble material. Thefiltrate was allowed to cool to ambient temperature. The resultingcrystals were filtered, washed with anhydrous diethyl ether, and driedunder vacuum at 40° C. to yield 1.20 g (47.0%) of a white, crystallinepowder, mp 148-150° C.

Sample No. 1 exhibits a log P of 1.924, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier. The sample exhibits a Ki of 83 nM. The low bindingconstant indicates that the compound exhibits good high affinity bindingto certain CNS nicotinic receptors.

Sample No. 1 exhibits an EC₅₀ value of 6600 nM and an E_(max) value of113% for dopamine release, indicating that the compound inducesneurotransmitter release thereby exhibiting known nicotinicpharmacology. The sample exhibits an EC₅₀ value of 3100 nM and anE_(max) value of 35% in the rubidium ion flux assay, indicating that thecompound effectively induces activation of CNS nicotinic receptors.

Sample No. 1 exhibits an E_(max) of 13% (at a concentration of 100 μM)at muscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. The sample exhibits an E_(max) of62% (at a concentration of 100 uM) at ganglionic-type receptors. Atcertain levels the compound shows CNS effects to a significant degreebut show neither undesirable muscle nor ganglion effects to anysignificant degree. The compound begins to cause muscle and ganglioneffects only when employed in amounts of several times those required toactivate rubidium ion flux and dopamine release, thus indicating a lackof certain undesirable side effects in subjects receiving administrationof that compound.

EXAMPLE 8

Sample No. 2 is (2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-aminehemigalactarate, which was prepared in accordance with the followingtechniques:

(2S)-4-Penten-2-ol

(2S)-4-Penten-2-ol was prepared from (S)-(−)-propylene oxide using aprocedure similar to that described for the preparation of(2R)-4-penten-2-ol from (R)-(+)-propylene oxide as detailed in A.Kalivretenos, J. K. Stille, and L. S. Hegedus, J. Org. Chem. 56: 2883(1991). Thus, a 1.0M solution of vinylmagnesium bromide in THF (129 mL,129.0 mmol) was slowly added to a suspension of copper(I) iodide (2.46g, 12.92 mmol) in dry THF (40 mL, distilled from sodium andbenzophenone) at −25° C. After stirring 5 min, a solution of(S)-(−)-propylene oxide (5.00 g, 86.1 mmol) in dry THF (5 mL) was added.The mixture was allowed to warm to −10° C. and placed in a freezer at 0°C. for 12 h. The mixture was stirred for an additional 1 h at 0° C. andpoured into a mixture of saturated ammonium chloride solution (100 mL)and ice (100 g). The mixture was stirred for 4 h and extracted withether (3×100 mL). The combined ether extracts were dried (K₂CO₃),filtered, and concentrated under reduced pressure by rotary evaporationat 0° C. The resulting brown oil was vacuum distilled to yield 5.86 g(79.1%) of a colorless distillate, bp 37-39° C. at 9 mm Hg.

(2S)-(4E)-5-(3-Pyridyl)-4-penten-2-ol

A mixture of 3-bromopyridine (11.22 g, 70.58 mmol), (2S)-4-penten-2-ol(5.00 g, 58.05 mmol), palladium(II) acetate (527 mg, 2.35 mmol),tri-o-tolylphosphine (1.79 g, 5.88 mmol), triethylamine (30 mL, 216mmol) and acetonitrile (30 mL) was heated in a sealed glass tube at130-140° C. for 8 h. The reaction mixture was cooled to ambienttemperature. The solvent was removed under reduced pressure on a rotaryevaporator. Water (20 mL) was added and the mixture was extracted withchloroform (4×50 mL). The combined chloroform extracts were dried(K₂CO₃), filtered, and concentrated by rotary evaporation, producing apale-yellow oil (6.00 g). The crude product was purified by columnchromatography over silica gel, eluting with chloroform-acetone (95:5,v/v). Selected fractions were combined and concentrated by rotaryevaporation, affording 3.95 g (41.7%) of a pale-yellow oil.

(2S)-(4E)-5-(3-Pyridyl)-4-penten-2-ol p-Toluenesulfonate

Under a nitrogen atmosphere, p-toluenesulfonyl chloride (7.01 g, 36.77mmol) was added to a stirring solution of(2S)-(4E)-5-(3-pyridyl)-4-penten-2-ol (3.00 g, 18.38 mmol) in drytriethylamine (20 mL) at 0° C. After stirring and warning to ambienttemperature over 18 h, the mixture was stirred with cold, saturatedNaHCO₃ solution (50 mL) for 1 hour and extracted with chloroform (3×50mL). The combined chloroform extracts were dried (K₂CO₃), filtered, andconcentrated by rotary evaporation to afford a thick, dark-brown mass(˜7 g). The crude product was purified by column chromatography onsilica gel, eluting with chloroform-acetone (98:2, v/v) to afford 4.00 g(68.6%) of a light-brown syrup.

(2R)-(4E)-N-Methyl-5-(3-pyridyl)-4-penten-2-amine

A mixture of (2S)-(4E)-5-(3-pyridyl)-4-penten-2-ol p-toluenesulfonate(3.80 g, 11.97 mmol) and methylamine (20 mL, 2.0M solution in THF) washeated at 100-110° C. for 8 h in a sealed glass tube. The mixture wascooled to ambient temperature and concentrated under reduced pressure ona rotary evaporator. The resulting brown syrup was diluted withsaturated NaHCO₃ solution (25 mL) and extracted with chloroform (4×25mL). The combined chloroform extracts were dried (K₂CO₃), filtered, andconcentrated by rotary evaporation to afford a thick, brown syrup (2.00g). The crude product was purified by column chromatography on silicagel, eluting with chloroform-methanol (95:5, v/v). Selected fractionswere combined, concentrated by rotary evaporation affording a 800 mg(37.9%) of a pale-yellow oil.

(2R)-(4E)-N-Methyl-5-(3-pyridyl)-4-penten-2-amine Hemigalactarate

Galactaric acid (328.0 mg, 1.56 mmol) and(2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine (600.0 mg, 3.40 mmol)were dissolved in 2-propanol (5 mL) and water (0.2 mL), assisted byheating and sonication. The hot solution was filtered to remove someinsoluble material. The solvent was removed on a rotary evaporator, andthe residue was dried under high vacuum, producing a cream-coloredsyrup. The syrup was dissolved in dry 2-propanol (5 mL) and cooled at 4°C. The resulting precipitate was filtered and dried under high vacuum toyield 700 mg (79.7%) of an off-white, crystalline powder, mp 131-134° C.

Sample No. 2 exhibits a log P of 1.924, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier. The sample exhibits a Ki of 520 nM, indicating thatthe compound exhibits binding to certain CNS nicotinic receptors.

Sample No. 2 exhibits an EC₅₀ value of 27400 nM and an E_(max) value of76% for dopamine release, indicating that the compound inducesneurotransmitter release thereby exhibiting known nicotinicpharmacology. The sample exhibits an EC₅₀ value of 4390 nM and anE_(max) value of 32% in the rubidium ion flux assay, indicating that thecompound induces activation of CNS nicotinic receptors.

Sample No. 2 exhibits an E_(max) of 0% (at a concentration of 100 uM) atmuscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. Sample No. 1 exhibits an E_(max) of36% (at a concentration of 100 uM) at ganglionic-type receptors. Thecompound has the capability to activate human CNS receptors withoutactivating muscle-type and ganglionic-type nicotinic acetylcholinereceptors to any significant degree. Thus, there is provided atherapeutic window for utilization in the treatment of CNS disorders.That is, at certain levels the compound shows CNS effects to asignificant degree but does not show undesirable muscle and ganglioneffects to any significant degree.

EXAMPLE 9

Sample No. 3 is (2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-aminehemigalactarate, which was prepared in accordance with the followingtechniques:

(2R)-4-Penten-2-ol

(2R)-4-Penten-2-ol was prepared in 82.5% yield from (R)-(+)-propyleneoxide according to procedures set forth in A. Kalivretenos, J. K.Stille, and L. S. Hegedus, J. Org. Chem. 56: 2883 (1991).

(2R)-(4E)-5-(3-Pyridyl)-4-penten-2-ol

A mixture of 3-bromopyridine (9.17 g, 58.04 mmol), (2R)-4-penten-2-ol(6.00 g, 69.65 mmol), palladium(II) acetate (130 mg, 0.58 mmol),tri-o-tolylphosphine (710 mg, 2.32 mmol), triethylamine (34.7 mL, 249.5mmol), and acetonitrile (35 mL) was heated in a sealed glass tube at140° C. for 14 h. The reaction mixture was cooled to ambienttemperature, diluted with water, and extracted with chloroform (3×200mL). The combined chloroform extracts were dried over sodium sulfate,filtered, and concentrated by rotary evaporation to give 6.17 g (65.2%)of a pale-yellow oil.

(2R)-(4E)-5-(3-Pyridyl)-4-penten-2-ol p-Toluenesulfonate

To a stirring solution of (2R)-(4E)-5-(3-pyridyl)-4-penten-2-ol (6.00 g,36.81 mmol) in dry pyridine (30 mL) at 0° C. was added p-toluenesulfonylchloride (21.05 g, 110.43 mmol). The reaction mixture was stirred for 24h at ambient temperature. The pyridine was removed by rotaryevaporation. Toluene (50 mL) was added to the residue and subsequentlyremoved by rotary evaporation. The crude product was stirred with asaturated solution of sodium bicarbonate (100 mL) and extracted withchloroform (3×100 mL). The combined chloroform extracts were dried oversodium sulfate, filtered, and concentrated by rotary evaporation to give11.67 g (84.0%) of a dark-brown, viscous oil.

(2S)-(4E)-N-Methyl-5-(3-pyridyl)-4-penten-2-amine

A mixture of (2R)-(4E)-5-(3-pyridyl)-4-penten-2-ol p-toluenesulfonate(9.00 g, 28.35 mmol), methylamine (200 mL, 40% solution in water), andethyl alcohol (10 mL) was stirred at ambient temperature for 18 h. Theresulting solution was extracted with chloroform (3×100 mL). Thecombined chloroform extracts were dried over sodium sulfate, filtered,and concentrated by rotary evaporation. The crude product was purifiedby column chromatography over aluminum oxide, eluting with ethylacetate-methanol (7:3, v/v). Selected fractions were combined andconcentrated by rotary evaporation, producing an oil. Furtherpurification by vacuum distillation furnished 1.20 g (24.0%) of acolorless oil, bp 90-100° C. at 0.5 mm Hg.

(2S)-(4E)-N-Methyl-5-(3-pyridyl)-4-penten-2-amine Hemigalactarate

(2S)-(4E)-N-Methyl-5-(3-pyridyl)-4-penten-2-amine (800 mg, 4.54 mmol)was dissolved in ethyl alcohol (20 mL), assisted by warming to 60° C.The warm solution was treated with galactaric acid (477 mg, 2.27 mmol)in one portion, followed by the dropwise addition of water (0.5 mL). Thesolution was filtered while hot to remove some insoluble material. Thefiltrate was allowed to cool to ambient temperature. The resultingcrystals were filtered, washed with anhydrous diethyl ether, and driedunder vacuum at 40° C. to yield 830 mg (65.4%) of an off-white,crystalline powder, mp 141-143° C.

Sample No. 3 exhibits a log P of 1.924, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier. The sample exhibits a Ki of 34 nM. The low bindingconstant indicates that the compound exhibits good high affinity bindingto certain CNS nicotinic receptors.

Sample No. 3 exhibits an EC₅₀ value of 2600 nM and an E_(max) value of162% for dopamine release, indicating that the compound effectivelyinduces neurotransmitter release thereby exhibiting known nicotinicpharmacology. The sample exhibits an EC₅₀ value of 45 nM and an E_(max)value of 33% in the rubidium ion flux assay, indicating that thecompound effectively induces activation of CNS nicotinic receptors.

Sample No. 3 exhibits an E_(max) of 0% (at a concentration of 100 uM) atmuscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. The sample exhibits an E_(max) of18% (at a concentration of 100 uM) at ganglionic-type receptors. Thecompound has the capability to activate human CNS receptors withoutactivating muscle-type and ganglionic-type nicotinic acetylcholinereceptors to any significant degree. Thus, there is provided atherapeutic window for utilization in the treatment of CNS disorders.That is, at certain levels the compound shows CNS effects to asignificant degree but does not show undesirable muscle or ganglioneffects to any significant degree.

EXAMPLE 10

Sample No. 4 is(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-aminehemigalactarate, which was prepared in accordance with the followingtechniques:

4-Penten-2-ol p-Toluenesulfonate

Under a nitrogen atmosphere, p-toluenesulfonyl chloride (16.92 g, 88.75mmol) was added to a cold (2° C.), stirring solution of 4-penten-2-ol(7.28 g, 84.52 mmol) in pyridine (60 mL). The solution was stirred at2-5° C. for 2 h and allowed to warm to ambient temperature over severalhours. The mixture, containing white solids, was poured into cold 3M HClsolution (250 mL) and extracted with CHCl₃ (4×75 mL). The combined CHCl₃extracts were washed with 3M HCl solution (4×100 mL), saturated NaClsolution (2×50 mL), dried (Na₂SO₄), filtered, concentrated on a rotaryevaporator, and further dried under high vacuum to afford 17.38 g(85.6%) of a light-amber oil.

N-Methyl-4-penten-2-amine

A glass pressure tube was charged with 4-penten-2-ol p-toluenesulfonate(17.30 g, 71.99 mmol) followed by a 40% solution of aqueous methylamine(111.85 g, 1.44 mol). The tube was sealed, and the mixture was stirredand heated at 122° C. for 16 h and allowed to cool to ambienttemperature. After further cooling to 0-5° C., the light-yellow solutionwas saturated with solid NaCl and extracted with diethyl ether (6×40 mL,inhibitor-free). The combined light-yellow ether extracts were dried(Na₂SO₄) and filtered. The ether was removed by distillation atatmospheric pressure using a 6-inch Vigreaux column and a short-pathdistillation apparatus. The residual light-yellow oil was distilled atatmospheric pressure collecting 3.72 g (52.1%) of a colorless oil, bp75-105° C.

N-Methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine

Di-tert-butyl dicarbonate (6.84 g, 31.35 mmol) was quickly added inseveral portions to a cold (0-5° C.), stirring solution ofN-methyl-4-penten-2-amine (3.66 g, 25.68 mmol) in dry THF (25 mL,freshly distilled from sodium and benzophenone). The resultinglight-yellow solution was stirred and allowed to warm to ambienttemperature over several hours. The solution was concentrated on arotary evaporator. The resulting oil was vacuum distilled using ashort-path distillation apparatus, collecting 5.22 g (88.4%) of analmost colorless oil, bp 85-86° C. at 5.5 mm Hg.

5-Bromo-3-isopropoxypyridine can be prepared by two different methods(Method A and Method B) as described below.

5-Bromo-3-isopropoxypyridine (Method A)

Potassium metal (6.59 g, 168.84 mmol) was dissolved in dry 2-propanol(60.0 mL) under nitrogen. The resulting potassium isopropoxide washeated with 3,5-dibromopyridine (20.00 g, 84.42 mmol) and copper powder(1 g, 5% by weight of 3,5-dibromopyridine) at 140° C. in a sealed glasstube for 14 h. The reaction mixture was cooled to ambient temperatureand extracted with diethyl ether (4×200 mL). The combined ether extractswere dried over sodium sulfate, filtered, and concentrated by rotaryevaporation. The crude product obtained was purified by columnchromatography over aluminum oxide, eluting with ethyl acetate-hexane(1:9, v/v). Selected fractions were combined and concentrated by rotaryevaporation, producing a pale-yellow oil (12.99 g, 71.2%).

5-Bromo-3-isopropoxypyridine (Method B) 5-Bromonicotinamide

Under a nitrogen atmosphere, 5-bromonicotinic acid (10.10 g, 50.00 mmol)was dissolved in thionyl chloride (65.24 g, 0.55 mol), and the resultingsolution was stirred 45 min at ambient temperature. Excess thionylchloride was removed by distillation, and the residue was dried underhigh vacuum. The resulting solid was ground to a powder with a mortarand pestle under a nitrogen atmosphere and quickly added to a 28%solution of aqueous ammonia at 0° C. The mixture was stirred briefly at0° C. and then at ambient temperature for 3 h. The crude product wasfiltered, dried, and recrystallized from toluene-ethanol (1:1, v/v) togive 6.92 g (68.9%) of 5-bromonicotinamide, mp 210-213° C. (lit. mp219-219.5° C., see C. V. Greco et al., J. Heteocyclic Chem. 7(4): 761(1970)).

3-Amino-5-bromopyridine

Sodium hydroxide (2.50 g, 62.50 mmol) was added to a cold (0° C.),stirring suspension of calcium hypochlorite solution (1.53 g, 7.50 mmolof 70% solution) in water (35 mL). The mixture was stirred 15 min at 0°C. and filtered. The clarified filtrate was cooled and stirred in anice-salt bath while 5-bromonicotinamide (3.03 g, 15.1 mmol) was added inone portion. The suspension was stirred 2 h at 0° C., warmed to ambienttemperature, and heated on a steam bath for 1 h. After cooling, themixture was extracted with CHCl₃ (2×50 mL). The combined CHCl₃ extractswere dried (Na₂SO₄), filtered, and concentrated on a rotary evaporatorproducing 1.42 g of a light-yellow solid. The aqueous layer was adjustedto pH 8 with 6M HCl solution and extracted with CHCl₃ (2×50 mL). Thecombined CHCl₃ extracts were dried (Na₂SO₄), filtered, and concentratedon a rotary evaporator, affording 0.98 g of a brown solid. Based uponTLC analysis (toluene-ethanol (3:1, v/v)), both crude products werecombined to give 2.40 g which was dissolved in ethanol (10 mL) andfiltered to remove a small amount of a light-yellow solid (80 mg, mp225-227° C.). The filtrate was concentrated on a rotary evaporator, andthe residue was dissolved in 2-propanol (6 mL), filtered, and cooled to5° C. The resulting precipitate was filtered and dried to give a smallamount of a tan solid (65 mg, mp 63-64° C.). The filtrate wasconcentrated on a rotary evaporator, and the residue was dissolved intoluene (5 mL), assisted by heating, and cooled to 5° C. The resultingprecipitate was filtered and dried under vacuum to give 1.80 g of abrown, crystalline solid, mp 65-67° C. By concentrating the filtrate andcooling, a second crop of 0.27 g of a brown solid, mp 64-66° C. (lit. mp69-69.5° C., see C. V. Greco et al., J. Heteocyclic Chem. 7(4): 761(1970)) was obtained, bringing the total yield to 2.07 g (79.3%).

5-Bromo-3-isopropoxypyridine

A slurry of 5-amino-3-bromopyridine (1.29 g, 7.46 mmol) in 6M HClsolution (5 mL) was stirred 30 min at ambient temperature. The mixturewas concentrated under high vacuum, and the residue was vacuum dried for15 h at 50° C., affording a tan solid. The solid was slurried in2-propanol (25 mL), and treated with isoamyl nitrite (1.70 g, 15.00mmol). The mixture was stirred and heated under reflux for 1.5 h. Thesolution was concentrated by rotary evaporation, and the residue waspartitioned between diethyl ether and 1M NaOH solution. The aqueouslayer was separated and extracted with ether. The combined etherextracts were dried (Na₂SO₄), filtered, and concentrated by rotaryevaporation producing an orange oil (2.03 g). The oil was purified byvacuum distillation, collecting the fraction with bp 105-115° C. at 9 mmHg. The distilled product was further purified by column chromatographyon silica gel, eluting with 10-20% (v/v) diethyl ether in hexane.Selected fractions, based upon TLC analysis (R_(f) 0.40 in hexane-ether,(4:1, v/v)) were combined and concentrated by rotary evaporation to give566.0 mg (35.2%) of a clear, colorless oil.

(4E)-N-Methyl-N-(tert-butoxycarbonyl)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine

Under a nitrogen atmosphere, a mixture of 5-bromo-3-isopropoxypyridine(847.0 mg, 3.92 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine(784.7 mg, 3.94 mmol), palladium(II) acetate (9.0 mg, 0.04 mmol),tri-o-tolylphosphine (50.0 mg, 0.16 mmol), triethylamine (0.73 g, 7.21mmol), and anhydrous acetonitrile (2 mL) was stirred and heated underreflux at 80° C. for 20 h. The mixture containing solids was cooled,diluted with water (10 mL), and extracted with CHCl₃ (3×10 mL). Thecombined CHCl₃ extracts were dried (Na₂SO₄), filtered, and concentratedby rotary evaporation to give an oily residue (1.56 g). The crudeproduct was purified by column chromatography on silica gel, elutingwith 25→40% (v/v) ethyl acetate in hexane. Selected fractions containingthe product were combined and concentrated to give 1.15 g (87.8%) of alight-amber oil.

(4E)-N-Methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine

Under a nitrogen atmosphere, a cold (0-5° C.), stirring solution of(4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine(150.0 mg, 0.45 mmol) in anisole (2.25 mL) was treated withtrifluoroacetic acid (1.49 g, 13.79 mmol) in one portion. The resultingsolution was stirred for 15 min at 0-5° C. TLC analysis on silica gel(EtOAc-hexane (3:1, v/v) and CH₃OH-Et₃N (97.5:2.5, v/v)) indicatedalmost complete reaction. After stirring for an additional 15 min, thesolution was concentrated on a rotary evaporator, followed by furtherdrying under vacuum at 0.5 mm Hg to give 278 mg of a dark-yellow oil.The oil was cooled (0-5° C.), basified with 10% NaOH solution (2 mL) topH 12, and saturated NaCl solution (5 mL) was added. The mixture wasextracted with CHCl₃ (5×3 mL). The combined CHCl₃ extracts were washedwith saturated NaCl solution (5 mL), dried (Na₂SO₄), filtered,concentrated by rotary evaporation, followed by further drying at 0.5 mmHg to give 104.7 mg of a light-yellow, slightly orange oil. The crudeproduct was purified by column chromatography on silica gel (20 g),eluting with CH₃OH-Et₃N (100:2, v/v). Selected fractions containing theproduct (R_(f) 0.37) were combined and concentrated on a rotaryevaporator to afford 72.3 mg of a yellow oil. The oil was dissolved inCHCl₃ (25 mL), and the CHCl₃ solution was dried (Na₂SO₄), filtered,concentrated by rotary evaporation, and vacuum dried to give 69.3 mg(66.2%) of a yellow oil.

(4E)-N-Methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amineHemigalactarate

(4E)-N-Methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine (69.3 mg, 0.23mmol) was dissolved in CH₃OH (1.5 mL), assisted by heating. The warmsolution was treated with galactaric acid (24.3 mg, 0.12 mmol), followedby water (0.3 mL). The resulting solution was warmed and filteredthrough glass wool to remove a few insoluble particles, washing thefilter plug with 0.4 mL of a CH₃OH—H₂O (4:1, v/v) solution. The filtratewas diluted with CH₃OH (1.5 mL), and the light-yellow solution wasstored at 5° C. for 15 h. No precipitate had formed; therefore, thesolution was concentrated on a rotary evaporator. The resulting solidswere triturated with anhydrous diethyl ether (3×6 mL). The product wasdried under a stream of nitrogen, dried under high vacuum, followed byfurther vacuum drying at 45° C. for 15 h to afford 73.0 mg (93.1%) of anoff-white powder, mp 144-146.5° C.

Sample No. 4 exhibits a log P of 2.957, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier. The sample exhibits a Ki of 10 nM. The low bindingconstant indicates that the compound exhibits good high affinity bindingto certain CNS nicotinic receptors.

Sample No. 4 exhibits an EC₅₀ value of 100 nM and an E_(max) value of57% for dopamine release, indicating that the compound effectivelyinduces neurotransmitter release thereby exhibiting known nicotinicpharmacology. The sample exhibits an EC₅₀ value of 100 mM and an E_(max)value of 60% in the rubidium ion flux assay, indicating that thecompound effectively induces activation of CNS nicotinic receptors.

Sample No. 4 exhibits an E_(max) of 15% (at a concentration of 100 uM)at muscle-type receptors, indicating that the compound does notsignificantly induce activation of muscle-type receptors. The sampleexhibits an E_(max) of 36% (at a concentration of 100 uM) atganglionic-type receptors. The compound has the capability to activatehuman CNS receptors without activating muscle-type and ganglionic-typenicotinic acetylcholine receptors to any significant degree. Thus, thereis provided a therapeutic window for utilization in the treatment of CNSdisorders. That is, at certain levels the compound shows CNS effects toa significant degree but does not show undesirable muscle and ganglioneffects to any significant degree. The compound begins to cause muscleeffects and ganglion effects only when employed in amounts greater thanthose required to activate rubidium ion flux and dopamine release, thusindicating a lack of undesirable side effects in subjects receivingadministration of this compound.

EXAMPLE 11

Sample No. 5 is(2R)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-aminehemigalactarate, which was prepared in accordance with the followingtechniques:

(2S)-4-Penten-2-ol

(2S)-4-Penten-2-ol was prepared from (S)-(−)-propylene oxide using aprocedure similar to that described for the preparation of(2R)-4-penten-2-ol from (R)-(+)-propylene oxide as detailed in A.Kalivretenos, J. K. Stille, and L. S. Hegedus, J. Org. Chem. 56: 2883(1991). Thus, a 1.0M solution of vinylmagnesium bromide in THF (129 mL,129.0 mmol) was slowly added to a suspension of copper(I) iodide (2.46g, 12.92 mmol) in dry THF (40 mL, distilled from sodium andbenzophenone) at −25° C. After stirring 5 min, a solution of(S)-(−)-propylene oxide (5.00 g, 86.1 mmol) in dry THF (5 mL) was added.The mixture was allowed to warm to −10° C. and placed in a freezer at 0°C. for 12 h. The mixture was stirred for an additional 1 h at 0° C. andpoured into a mixture of saturated ammonium chloride solution (100 mL)and ice (100 g). The mixture was stirred for 4 h and extracted withether (3×100 mL). The combined ether extracts were dried (K₂CO₃),filtered, and concentrated under reduced pressure by rotary evaporationat 0° C. The resulting brown oil was vacuum distilled to yield 5.86 g(79.1%) of a colorless distillate, bp 37-39° C. at 9 mm Hg.

(2S)-(4E)-5-(5-Isopropoxy-3-pyridyl)-4-penten-2-ol

A mixture of 5-bromo-3-isopropoxypyridine (12.56 g, 58.13 mmol),(2S)-4-penten-2-ol (5.00 g, 58.05 mmol), palladium(II) acetate (130 mg,0.58 mmol), tri-o-tolylphosphine (706 mg, 2.32 mmol), triethylamine (35mL, 252 mmol) and acetonitrile (35 mL) was heated in a sealed glass tubeat 130-140° C. for 8 h. The reaction mixture was cooled to ambienttemperature. The solvent was removed under reduced pressure on a rotaryevaporator. Water (50 mL) was added and the mixture was extracted withchloroform (3×50 mL). The combined chloroform extracts were dried(K₂CO₃), filtered, and concentrated by rotary evaporation. The crudeproduct was purified by column chromatography over silica gel, elutingwith chloroform-acetone (95:5, v/v). Selected fractions were combinedand concentrated by rotary evaporation, producing 7.80 g (60.7%) of apale-yellow oil.

(2S)-(4E)-5-(5-Isopropoxy-3-pyridyl)-4-penten-2-ol p-Toluenesulfonate

Under a nitrogen atmosphere, p-toluenesulfonyl chloride (11.45 g, 60.06mmol) was added to a stirring solution of(2S)-(4E)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-ol (7.00 g, 31.63 mmol)in dry triethylamine (30 mL) at 0° C. After stirring and warming toambient temperature over 18 h, the mixture was concentrated on a rotaryevaporator. The crude product was stirred with saturated NaHCO₃ solution(100 mL) for 1 hour and extracted with chloroform (3×50 mL). Thecombined chloroform extracts were dried (K₂CO₃), filtered, andconcentrated by rotary evaporation to afford 10.00 g (84.2%) as adark-brown oil, which was used without further purification.

(2R)-(4E)-N-Methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine

A mixture of (2S)-(4E)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-olp-toluenesulfonate (10.00 g, 26.63 mmol) and methylamine (50 mL, 2.0Msolution in THF) was heated at 100° C. for 10 h in a sealed glass tube.The mixture was cooled to ambient temperature and concentrated underreduced pressure on a rotary evaporator. The crude product was treatedwith saturated NaHCO₃ solution (50 mL) and extracted with chloroform(4×50 mL). The combined chloroform extracts were dried (K₂CO₃),filtered, and concentrated by rotary evaporation to afford a dark-brownoil (3.50 g). The crude product was purified by repeated (twice) columnchromatography on silica gel, eluting with chloroform-methanol (95:5,v/v). Selected fractions were combined, concentrated by rotaryevaporation affording a light-brown oil (2.50 g). The oil was furtherpurified by vacuum distillation using a short-path distillationapparatus, collecting 2.05 g (32.9%) of a colorless oil, bp 98-100° C.at 0.04 mm Hg.

(2R)-(4E)-N-Methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amineHemigalactarate

Galactaric acid (314.0 mg, 1.49 mmol) was dissolved in 2-propanol (10mL) and water (˜1 mL), assisted by heating and sonicating over a periodof 10 min. A solution of(2R)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine (700.3mg, 2.99 mmol) in 2-propanol (10 mL) was then added, followed byadditional sonicating and heating at 60° C. for 10 min. The hot solutionwas filtered to remove some insoluble material. The solvent was removedon a rotary evaporator; the resulting light-brown syrup was dissolved indry 2-propanol (5 mL) and cooled at 4° C. The resulting precipitate wasfiltered and dried under high vacuum to yield 657 mg (64.8%) of anoff-white, crystalline powder, mp 150-153° C.

Sample No. 5 exhibits a log P of 2.957, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier. The sample exhibits a Ki of 62 nM. The low bindingconstant indicates that the compound exhibits good high affinity bindingto certain CNS nicotinic receptors.

Sample No. 5 exhibits an EC₅₀ value of 634 nM and an E_(max) value of38% for dopamine release, indicating that the compound effectivelyinduces neurotransmitter release thereby exhibiting known nicotinicpharmacology. The sample exhibits an EC₅₀ value of 88 nM and an E_(max)value of 14% in the rubidium ion flux assay, indicating that thecompound induces activation of CNS nicotinic receptors.

Sample No. 5 exhibits an E_(max) of 0% (at a concentration of 100 uM) atmuscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. The sample exhibits an E_(max) of14% (at a concentration of 100 uM) at ganglionic-type receptors. Thecompound has the capability to activate human CNS receptors withoutactivating muscle-type and ganglionic-type nicotinic acetylcholinereceptors to any significant degree. Thus, there is provided atherapeutic window for utilization in the treatment of CNS disorders.That is, at certain levels the compound shows CNS effects to asignificant degree but does not show undesirable muscle and gangliaeffects to any significant degree.

EXAMPLE 12

Sample No. 6 is(2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-aminehemigalactarate, which was prepared in accordance with the followingtechniques:

(2R)-4-Penten-2-ol

(2R)-4-Penten-2-ol was prepared in 82.5% yield from (R)-(+)-propyleneoxide according to procedures set forth in A. Kalivretenos, J. K.Stille, and L. S. Hegedus, J. Org. Chem. 56: 2883 (1991).

(2R)-(4E)-5-(5-Isopropoxy-3-pyridyl)-4-penten-2-ol

A mixture of 5-bromo-3-isopropoxypyridine (10.26 g, 47.50 mmol),(2R)-4-penten-2-ol (4.91 g, 57.00 mmol), palladium(II) acetate (106 mg,0.47 mmol), tri-o-tolylphosphine (578 mg, 1.90 mmol), triethylamine(28.46 mL, 204.25 mmol), and acetonitrile (30 mL) was heated in a sealedglass tube at 140° C. for 14 h. The reaction mixture was cooled toambient temperature, diluted with water, and extracted with chloroform(3×200 mL). The combined chloroform extracts were dried over sodiumsulfate, filtered, and concentrated by rotary evaporation to give apale-yellow oil (8.92 g, 85.0%).

(2R)-(4E)-5-(5-Isopropoxy-3-pyridyl)-4-penten-2-ol p-Toluenesulfonate

To a stirred solution of(2R)-(4E)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-ol (8.50 g, 38.46 mmol)in dry pyridine (30 mL) at 0° C. was added p-toluenesulfonyl chloride(14.67 g, 76.92 mmol). The reaction mixture was stirred for 24 h atambient temperature. The pyridine was removed by rotary evaporation.Toluene (50 mL) was added to the residue and removed by rotaryevaporation. The crude product was stirred with a saturated solution ofsodium bicarbonate (100 mL) and extracted with chloroform (3×100 mL).The combined chloroform extracts were dried over sodium sulfate,filtered, and concentrated by rotary evaporation to yield a dark-brown,viscous oil (11.75 g, 81.5%).

(2S)-(4E)-N-Methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine

A mixture of (2R)-(4E)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-olp-toluenesulfonate (11.00 g, 29.33 mmol), methylamine (200 mL, 40%solution in water), and ethyl alcohol (10 mL) was stirred at ambienttemperature for 18 h. The resulting solution was extracted withchloroform (3×100 mL). The combined chloroform extracts were dried oversodium sulfate, filtered, and concentrated by rotary evaporation. Thecrude product was purified by column chromatography over aluminum oxide,eluting with ethyl acetate-methanol (7:3, v/v). Selected fractions werecombined and concentrated by rotary evaporation, producing an oil.Further purification by vacuum distillation furnished 2.10 g (31.0%) ofa colorless oil, bp 90-100° C. at 0.5 mm Hg.

(2S)-(4E)-N-Methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amineHemigalactarate

(2S)-(4E)-N-Methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine (2.00 g,8.55 mmol) was dissolved in ethyl alcohol (20 mL), assisted by warmingto 70° C. The warm solution was treated with galactaric acid (900 mg,4.27 mmol) in one portion, followed by the dropwise addition of water(0.5 mL). The solution was filtered while hot to remove some insolublematerial. The filtrate was allowed to cool to ambient temperature. Theresulting crystals were filtered, washed with anhydrous diethyl ether,and dried under vacuum at 40° C. to yield a white, crystalline powder(750 mg, 26.0%), mp 140-143° C.

Sample No. 6 exhibits a log P of 2.957, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier. The sample exhibits a Ki of 11 nM. The low bindingconstant indicates that the compound exhibits good high affinity bindingto certain CNS nicotinic receptors.

Sample No. 6 exhibits an EC₅₀ value of 106 nM and an E_(max) value of85% for dopamine release, indicating that the compound effectivelyinduces neurotransmitter release thereby exhibiting known nicotinicpharmacology. The sample exhibits an EC₅₀ value of 220 nM and an E_(max)value of 58% in the rubidium ion flux assay, indicating that thecompound effectively induces activation of CNS nicotinic receptors.

Sample No. 6 exhibits an E_(max) of 0% (at a concentration of 100 uM) atmuscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. The sample exhibits an E_(max) of0% (at a concentration of 100 mM) at ganglionic-type receptors. Thecompound has the capability to activate human CNS receptors withoutactivating muscle-type and ganglionic-type nicotinic acetylcholinereceptors to any significant degree. Thus, there is provided atherapeutic window for utilization in the treatment of CNS disorders.That is, at certain levels the compound shows CNS effects to asignificant degree but does not show undesirable muscle or gangliaeffects to any significant degree.

EXAMPLE 13

Sample No. 7 is (4E)-N-methyl-5-(5-bromo-3-pyridyl)-4-penten-2-amine,which was prepared in accordance with the following techniques:

(4E)-5-(5-Bromo-3-pyridyl)-4-penten-2-ol

A mixture of 3,5-dibromopyridine (23.60 g, 100.0 mmol), 4-penten-2-ol(10.8 g, 125.0 mmol), palladium(II) acetate (230 mg, 1.02 mmol),tri-o-tolylphosphine (1.20 g, 3.94 mmol), triethylamine (29.7 mL, 213.45mmol), and acetonitrile (40 mL) was heated in a sealed glass tube at140° C. for 14 h. The reaction mixture was cooled to ambienttemperature, diluted with water, and extracted with chloroform (3×200mL). The combined chloroform extracts were dried over sodium sulfate andfiltered. Removal of solvent by rotary evaporation, followed by columnchromatography over silica gel eluting with acetone-chloroform (1:9,v/v) furnished 8.10 g (34.0%) of a pale-yellow oil.

(4E)-N-Methyl-5-(5-bromo-3-pyridyl)-4-penten-2-amine

To a stirring solution of (4E)-5-(5-bromo-3-pyridyl)-4-penten-2-ol (3.14g, 13.0 mmol) in dry pyridine (30 mL) at 0° C. was addedp-toluenesulfonyl chloride (3.71 g, 19.5 mmol). The reaction mixture wasstirred for 24 h at ambient temperature. The pyridine was removed byrotary evaporation. Toluene (50 mL) was added to the residue andsubsequently removed by rotary evaporation. The crude product wasstirred with a saturated solution of sodium bicarbonate (100 mL) andextracted with chloroform (3×100 mL). The combined chloroform extractswere dried over sodium sulfate, filtered, and concentrated by rotaryevaporation to give (4E)-5-(5-bromo-3-pyridyl)-4-penten-2-olp-toluenesulfonate. The resulting tosylate was treated with excessmethylamine (40% solution in water), ethyl alcohol (10 mL), and stirredat ambient temperature for 18 h. The resulting solution was extractedwith chloroform (3×100 mL). The combined chloroform extracts were driedover sodium sulfate and filtered. Removal of solvent by rotaryevaporation followed by column chromatography over silica gel elutingwith chloroform-methanol (95:5, v/v) produced 1.50 g (45.0%) of apale-yellow oil.

Sample No. 7 exhibits a log P of 2.026, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier. The sample exhibits a Ki of 284 nM, indicating thatthe compound exhibits binding to certain CNS nicotinic receptors.

Sample No. 7 exhibits an EC₅₀ value of 202 nM and an E_(max) value of18% for dopamine release, indicating that the compound inducesneurotransmitter release thereby exhibiting known nicotinicpharmacology. The sample exhibits an E_(max) value of 0% in the rubidiumion flux assay, indicating that the compound exhibits selective effectsat certain CNS nicotinic receptors.

Sample No. 7 exhibits an E_(max) of 6% (at a concentration of 100 uM) atmuscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. The sample exhibits an E_(max) of8% (at a concentration of 100 uM) at ganglionic-type receptors. Thecompound has the capability to activate human CNS receptors withoutactivating muscle-type and ganglionic-type nicotinic acetylcholinereceptors to any significant degree. Thus, there is provided atherapeutic window for utilization in the treatment of CNS disorders.That is, at certain levels the compound shows CNS effects to asignificant degree but does not show undesirable muscle or gangliaeffects to any significant degree.

EXAMPLE 14

Sample No. 8 is (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-aminehemigalactarate, which was prepared in accordance with the followingtechniques:

5-Bromo-3-methoxypyridine

A mixture of 3,5-dibromopyridine (20.00 g, 84.42 mmol), sodium methoxide(11.40 g, 211.06 mmol), and copper powder (1 g, 5% by weight of3,5-dibromopyridine) in dry methanol was heated in a sealed glass tubeat 150° C. for 14 h. The reaction mixture was cooled to ambienttemperature and extracted with diethyl ether (4×200 mL). The combinedether extracts were dried over sodium sulfate, filtered, andconcentrated by rotary evaporation. The crude product was purified bycolumn chromatography over aluminum oxide, eluting with ethylacetate-hexane (1:9, v/v). Selected fractions were combined andconcentrated by rotary evaporation, producing 9.40 g (59.5%) of acolorless oil, which tended to crystallize upon cooling.

(4E)-5-(5-Methoxy-3-pyridyl)-4-penten-2-ol

A mixture of 5-bromo-3-methoxypyridine (4.11 g, 21.86 mmol),4-penten-2-ol (2.25 g, 26.23 mmol), palladium(II) acetate (49 mg, 0.22mmol), tri-o-tolylphosphine (266 mg, 0.87 mmol), triethylamine (13.71mL, 98.37 mmol), and acetonitrile (15 mL) was heated in a sealed glasstube at 140° C. for 14 h. The reaction mixture was cooled to ambienttemperature, diluted with water, and extracted with chloroform (3×200mL). The combined chloroform extracts were dried over sodium sulfate,filtered, and concentrated by rotary evaporation to give 3.53 g (70.3%)of a pale-yellow oil.

(4E)-5-(5-Methoxy-3-pyridyl)-4-penten-2-ol p-Toluenesulfonate

To a stirred solution of (4E)-5-(5-methoxy-3-pyridyl)-4-penten-2-ol(3.50 g, 18.13 mmol) in dry pyridine (15 mL) at 0° C. was addedp-toluenesulfonyl chloride (6.91 g, 36.27 mmol). The reaction mixturewas stirred for 24 h at ambient temperature. The pyridine was removed byrotary evaporation. Toluene (50 mL) was added to the residue andsubsequently removed by rotary evaporation. The crude product wasstirred with a saturated solution of sodium bicarbonate (100 mL) andextracted with chloroform (3×100 mL). The combined chloroform extractswere dried over sodium sulfate, filtered, and concentrated by rotaryevaporation to give 5.25 g (83.5%) of a dark-brown, viscous oil.

(4E)-N-Methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine

A mixture of (4E)-5-(5-methoxy-3-pyridyl)-4-penten-2-olp-toluenesulfonate (5.00 g, 14.41 mmol), methylamine (150 mL, 40%solution in water), and ethyl alcohol (10 mL) was stirred at ambienttemperature for 18 h. The resulting solution was extracted withchloroform (3×100 mL). The combined chloroform extracts were dried oversodium sulfate, filtered, and concentrated by rotary evaporation. Thecrude product was purified by column chromatography over aluminum oxide,eluting with ethyl acetate-methanol (7:3, v/v). Selected fractions werecombined and concentrated by rotary evaporation, producing an oil.Further purification by vacuum distillation furnished 1.25 g (41.8%) ofa colorless oil, bp 90-100° C. at 0.5 mm Hg.

(4E)-N-Methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine Hemigalactarate

(4E)-N-Methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine (1.20 g, 5.83mmol) was dissolved in ethyl alcohol (20 mL), assisted by warming to 60°C. The warm solution was treated with galactaric acid (610 mg, 2.91mmol) in one portion, followed by dropwise addition of water (0.5 mL).The solution was filtered while hot to remove some insoluble material.The filtrate was allowed to cool to ambient temperature. The resultingcrystals were filtered, washed with anhydrous diethyl ether, and driedunder vacuum at 40° C. to yield 1.05 g (58.0%) of a white, crystallinepowder, mp 143-145° C.

Sample No. 8 exhibits a log P of 2.025, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier. The sample exhibits a Ki of 22 nM. The low bindingconstant indicates that the compound exhibits good high affinity bindingto certain CNS nicotinic receptors.

Sample No. 8 exhibits an EC₅₀ value of 5000 nM and an E_(max) value of110% for dopamine release, indicating that the compound effectivelyinduces neurotransmitter release thereby exhibiting known nicotinicpharmacology.

Sample No. 8 exhibits an E_(max) of 10% (at a concentration of 100 uM)at muscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. The sample exhibits an E_(max) of2% (at a concentration of 100 uM) at ganglionic-type receptors. Thecompound has the capability to activate human CNS receptors withoutactivating muscle-type and ganglionic-type nicotinic acetylcholinereceptors to any significant degree. Thus, there is provided atherapeutic window for utilization in the treatment of CNS disorders.That is, at certain levels the compound shows CNS effects to asignificant degree but does not show undesirable muscle or ganglioneffects to any significant degree.

EXAMPLE 15

Sample No. 9 is (4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-aminehemigalactarate, which was prepared in accordance with the followingtechniques:

5-Bromo-3-ethoxypyridine

Under a nitrogen atmosphere, sodium (4.60 g, 200.0 mmol) was added toabsolute ethanol (100 mL) at 0-5° C., and the stirring mixture wasallowed to warm to ambient temperature over 18 h. To the resultingsolution was added 3,5-dibromopyridine (31.50 g, 133.0 mmol), followedby DMF (100 mL). The mixture was heated at 70° C. for 48 h. The brownmixture was cooled, poured into water (600 mL), and extracted with ether(3×500 mL). The combined ether extracts were dried (Na₂SO₄), filtered,and concentrated by rotary evaporation, producing 46.70 g of an oil.Purification by vacuum distillation afforded 22.85 g (85.0%) of an oil,bp 89-90° C. at 2.8 mm Hg, (lit. bp 111° C. at 5 mm Hg, see K. Clarke etal., J. Chem. Soc. 1885 (1960)).

(4E)-N-Methyl-N-(tert-butoxycarbonyl)-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine

Under a nitrogen atmosphere, a mixture of 5-bromo-3-ethoxypyridine (1.20g, 5.94 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (1.18g, 5.94 mmol), palladium(II) acetate (13.5 mg, 0.06 mmol),tri-o-tolylphosphine (73.1 mg, 0.24 mmol), triethylamine (1.5 mL, 10.8mmol), and anhydrous acetonitrile (3 mL) was stirred and heated underreflux at 80-85° C. for 28 h. The resulting mixture, containing beigesolids, was cooled to ambient temperature, diluted with water (20 mL),and extracted with CHCl₃ (3×20 mL). The combined light-yellow CHCl₃extracts were dried (Na₂SO₄), filtered, concentrated by rotaryevaporation, and vacuum dried producing a yellow oil (1.69 g). The crudeproduct was purified by column chromatography on silica gel (100 g),eluting with ethyl acetate-hexane (1:1, v/v). Selected fractionscontaining the product (R_(f) 0.20) were combined, concentrated byrotary evaporation, and the residue was vacuum dried to give 0.67 g(35.2%) of a light-yellow oil.

(4E)-N-Methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine

Under a nitrogen atmosphere, a cold (0-5° C.), stirring solution of(4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine(0.67 g, 2.09 mmol) in anisole (10 mL) was treated dropwise over 30 minwith trifluoroacetic acid (10.40 g, 91.17 mmol). The resulting solutionwas stirred for 45 min at 0-5° C. and was then concentrated by rotaryevaporation. The light-yellow oil was further dried under high vacuum at0.5 mm Hg. The resulting oil was cooled (0-5° C.), basified with 10%NaOH solution (10 mL), treated with saturated NaCl solution (7.5 mL),and extracted with CHCl₃ (4×10 mL). The combined light-yellow CHCl₃extracts were washed with saturated NaCl solution (20 mL), dried(Na₂SO₄), filtered, concentrated by rotary evaporation, followed byfurther drying at 0.5 mm Hg producing a brown oil (0.46 g). The crudeproduct was purified by column chromatography on silica gel (56 g),eluting with CH₃OH-Et₃N (98:2, v/v). Selected fractions containing theproduct (R_(f) 0.35) were combined and concentrated on a rotaryevaporator. The residue was dissolved in CHCl₃, and the CHCl₃ solutionwas dried (Na₂SO₄), filtered, concentrated by rotary evaporation, andvacuum dried to give 327.5 mg (71.0%) of a light-yellow oil.

(4E)-N-Methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine Hemigalactarate

To a solution of (4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine(151.4 mg, 0.68 mmol) in absolute ethanol (2.3 mL) was added galactaricacid (72.2 mg, 0.34 mmol). Water (0.5 mL) was added dropwise whilegently warming the light-brown solution. The solution was filteredthrough glass wool to remove a few insoluble particles, washing thefilter plug with ethanol-water (4:1, v/v) (1 mL). The filtrate wasdiluted with ethanol (3.4 mL), cooled to ambient temperature, andfurther cooled at 5° C. for 18 h. Because no precipitate had formed, thesolution was concentrated on a rotary evaporator. The resulting solidswere dried under high vacuum and recrystallized from 2-propanol-water.After cooling at 5° C. for 48 h the product was filtered, washed withcold 2-propanol, and vacuum dried at 45° C. for 6 h. Further vacuumdrying at ambient temperature for 18 h afforded 168 mg (76.1%) of awhite to off-white powder, mp 141-143.5° C.

Sample No. 9 exhibits a log P of 2.556, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier. The sample exhibits a Ki of 15 nM. The low bindingconstant indicates that the compound exhibits good high affinity bindingto certain CNS nicotinic receptors.

Sample No. 9 exhibits an EC₅₀ value of 520 nM and an E_(max) value of85% for dopamine release, indicating that the compound effectivelyinduces neurotransmitter release thereby exhibiting known nicotinicpharmacology. The sample exhibits an E_(max) value of 0% in the rubidiumion flux assay, indicating that the compound exhibits selective effectsat certain CNS nicotinic receptors.

Sample No. 9 exhibits an E_(max) of 21% (at a concentration of 100 uM)at muscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. The sample exhibits an E_(max) of9% (at a concentration of 100 uM) at ganglionic-type receptors. Thecompound has the capability to activate human CNS receptors withoutactivating muscle-type and ganglionic-type nicotinic acetylcholinereceptors to any significant degree. Thus, there is provided atherapeutic window for utilization in the treatment of CNS disorders.That is, at certain levels the compound shows CNS effects to asignificant degree but does not show undesirable muscle or gangliaeffects to any significant degree.

EXAMPLE 16

Sample No. 10 is(4E)-N-methyl-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine, which wasprepared in accordance with the following techniques:

(4E)-N-Methyl-N-(tert-butoxycarbonyl)-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine

A mixture of 2-amino-5-bromo-3-methylpyridine (1.41 g, 7.53 mmol),N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (1.50 g, 7.53 mmol),palladium(II) acetate (33.8 mg, 0.15 mmol), tri-o-tolylphosphine (183.2mg, 0.60 mmol), triethylamine (4.50 mL, 32.3 mmol), and anhydrousacetonitrile (8 mL) was stirred and heated at 130-132° C. in a sealedglass tube for 18 h. The mixture was further heated at 140° C. for 84 h.The resulting dark-brown solution was cooled to ambient temperature andconcentrated by rotary evaporation. The residue was diluted with water(25 mL) and extracted with CH₂Cl₂ (3×25 mL). The combined CH₂Cl₂extracts were dried (Na₂SO₄), filtered, concentrated by rotaryevaporation, and vacuum dried producing a dark-brown oil (2.84 g). Thecrude product was purified by column chromatography on silica gel (135g), eluting with ethyl acetate-hexane (3:1, v/v) to remove impurities,followed by elution with CH₃OH-Et₃N (98:2, v/v) to collect the product.Fractions containing the product (R_(f) 0.70) were combined anddissolved in CHCl₃. The CHCl₃ solution was dried (Na₂SO₄), filtered,concentrated by rotary evaporation, and vacuum dried to give 1.11 g(48.4%) of an amber-brown oil.

(4E)-N-Methyl-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine

Under a nitrogen atmosphere, trifluoroacetic acid (17.76 g, 155.76 mmol)was added dropwise, via addition funnel, over 30 min to a cold (0-5°C.), stirring solution of(4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine(1.11 g, 3.47 mmol) in anisole (15 mL). The resulting solution wasstirred for 45 min at 0-5° C. and was then concentrated by rotaryevaporation. The viscous, brown oil was further dried under high vacuumfor 18 h. The crude product was cooled (0-5° C.), basified with 10% NaOHsolution (10 mL), treated with saturated NaCl solution (10 mL), andextracted with CHCl₃ (5×10 mL). The combined CHCl₃ extracts were dried(Na₂SO₄), filtered, concentrated by rotary evaporation, followed byfurther drying under high vacuum yielding a dark-brown oil. The crudeproduct was purified by column chromatography on silica gel (50 g),eluting with CHCl₃—CH₃OH-Et₃N (4:1:1, v/v/v). Selected fractionscontaining the product (R_(f) 0.13) were combined and concentrated byrotary evaporation, and the residue was re-chromatographed on silica gel(50 g) eluting with CHCl₃-CH₃OH (7:3, v/v). Fractions containing theproduct (R_(f) 0.12) were combined and concentrated by rotaryevaporation. The residue was dissolved in CHCl₃, and the CHCl₃ solutionwas dried (Na₂SO₄), filtered, concentrated by rotary evaporation, andvacuum dried affording a yellow oil (0.087 g) which tended tocrystallize. The semi-crystalline material was dissolved in a warmsolution of hexane containing a small amount of ethyl acetate. The warmsolution was decanted from an insoluble gum. The solution was allowed tocool to ambient temperature and was further cooled at 5° C. for 18 h.The resulting crystalline solids were collected, washed with hexane, andvacuum dried at 40° C. for 16 h. The yield was 30.8 mg (4.3%) of alight-yellow powder, mp 78-81° C.

Sample No. 10 exhibits a log P of 1.333, and such a favorable log Pvalue indicates that the compound has the capability of passing theblood-brain barrier. The sample exhibits a Ki of 720 nM. The bindingconstant indicates that the compound exhibits high affinity binding tocertain CNS nicotinic receptors.

Sample No. 10 exhibits an EC₅₀ value of 100000 nM and an E_(max) valueof 200% for dopamine release, indicating that the compound inducesneurotransmitter release thereby exhibiting known nicotinicpharmacology.

Sample No. 10 exhibits an E_(max) of 0% (at a concentration of 100 μM)at muscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. The sample exhibits an E_(max) of0% (at a concentration of 100 uM) at ganglionic-type receptors. Thecompound has the capability to activate human CNS receptors withoutactivating muscle-type and ganglionic-type nicotinic acetylcholinereceptors to any significant degree. Thus, there is provided atherapeutic window for utilization in the treatment of CNS disorders.

EXAMPLE 17

Sample No. 11 is (4E)-N-methyl-5-(5-pyrimidinyl)-4-penten-2-aminehemigalactarate, which was prepared in accordance with the followingtechniques:

(4E)-N-Methyl-N-(tert-butoxycarbonyl)-5-(5-pyrimidinyl)-4-penten-2-ol

A glass pressure tube was charged with a mixture of 5-bromopyrimidine(1.28 g, 8.05 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine(1.60 g, 8.05 mmol), palladium(II) acetate (18.1 mg, 0.08 mmol),tri-o-tolylphosphine (98.6 mg, 0.32 mmol), triethylamine (3.00 mL, 21.5mmol), and anhydrous acetonitrile (6 mL). The tube was flushed withnitrogen and sealed. The mixture was stirred and heated at 90° C. for 64h, followed by further heating at 110° C. for 24 h. The resulting brownmixture was cooled to ambient temperature and concentrated by rotaryevaporation. The brown residue was diluted with water (25 mL) andextracted with CH₂Cl₂ (3×25 mL). The combined CH₂Cl₂ extracts were dried(Na₂SO₄), filtered, concentrated by rotary evaporation, and vacuum driedproducing a dark-brown oil (2.24 g). The crude product was purified bycolumn chromatography on silica gel (120 g), eluting with ethylacetate-hexane (3:1, v/v). Fractions containing the product (R_(f) 0.21)were combined, concentrated by rotary evaporation, and vacuum dried togive 1.05 g (46.9%) of a light-yellow oil.

(4E)-N-Methyl-5-(5-pyrimidinyl)-4-penten-2-ol

Under a nitrogen atmosphere, a stirring solution of(4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(5-pyrimidinyl)-4-penten-2-ol(881.2 mg, 3.18 mmol) in CHCl₃ (55 mL) was treated dropwise at ambienttemperature with iodotrimethylsilane (1.41 g, 7.03 mmol). The resultingsolution was stirred for 30 min. Methanol (55 mL) was added, and thesolution was stirred for an additional 1 h and was concentrated byrotary evaporation. With ice-bath cooling, the residue was basified with10% NaOH solution (10 mL), treated with saturated NaCl solution (10 mL),and extracted with CHCl₃ (8×10 mL). The combined CHCl₃ extracts weredried (Na₂SO₄), filtered, concentrated by rotary evaporation, followedby further drying under high vacuum producing a light-brown oil (0.50g). The crude product was purified by column chromatography on silicagel (50 g), eluting with CH₃OH—NH₄OH (20:1, v/v). Fractions containingthe product (R_(f) 0.43) were combined, concentrated by rotaryevaporation, and the residue was dissolved in CHCl₃. The CHCl₃ solutionwas dried (Na₂SO₄), filtered, concentrated by rotary evaporation, andvacuum dried affording 306.4 mg (54.4%) of a light-amber oil.

(4E)-N-Methyl-5-(5-pyrimidinyl)-4-penten-2-amine Hemigalactarate

To a warm solution of (4E)-N-methyl-5-(5-pyrimidinyl)-4-penten-2-amine(258.6 mg, 1.46 mmol) in absolute ethanol (2.3 mL) was added galactaricacid (153.3 mg, 0.73 mmol). Water (0.8 mL) was added, and the solutionwas heated to near reflux until most of the solids dissolved. Thesolution was filtered through glass wool to remove a few white,insoluble particles, washing the filter plug with a warm solution ofethanol-water (4:1, v/v) (1.1 mL). The filtrate was diluted with ethanol(6.5 mL), cooled to ambient temperature, and further cooled at 5° C. for48 h. The white precipitate was filtered, washed with cold ethanol, andvacuum dried at 40° C. for 18 h. The yield was 390.6 mg (94.8%) of afluffy, white, crystalline powder, mp 164-167° C.

Sample No. 11 is determined to exhibit a log P of 0.571, and such afavorable log P value indicates that the compound has the capability ofpassing the blood-brain barrier. The sample exhibits a Ki of 179 nM. Thelow binding constant indicates that the compound exhibits good highaffinity binding to certain CNS nicotinic receptors.

Sample No. 11 exhibits an EC₅₀ value of 1500 nM and an E_(max) value of80% for dopamine release, indicating that the compound effectivelyinduces neurotransmitter release thereby exhibiting known nicotinicpharmacology. The sample exhibits an EC₅₀ value of 100000 nM and anE_(max) value of 0% in the rubidium ion flux assay, indicating that thecompound exhibits selective effects at certain CNS nicotinic receptors.

Sample No. 11 exhibits an E_(max) of 0% (at a concentration of 100 uM)at muscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. The sample exhibits an E_(max) of13% (at a concentration of 100 uM) at ganglionic-type receptors. Thecompound has the capability to activate human CNS receptors withoutactivating muscle-type and ganglionic-type nicotinic acetylcholinereceptors to any significant degree. Thus, there is provided atherapeutic window for utilization in the treatment of CNS disorders.

The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. The invention is defined by the followingclaims, with equivalents of the claims to be included therein.

1. A method for the treatment or prophylaxis of attention deficitdisorder comprising administering a compound(2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl-4-penten-2-amine or apharmaceutically acceptable salt thereof.
 2. (canceled)
 3. The method ofclaim 1, wherein the attention deficit disorder is predominantlycombined type.
 4. The method of claim 1, wherein the attention deficitdisorder is predominantly inattentive type.
 5. The method of claim 1,wherein the attention deficit disorder is predominantlyhyperactive-impulsive type.